Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin-resistance and hyperglycemia

ABSTRACT

This invention provides compounds of Formula I having the structure  
                 
 
     A is hydrogen, halogen, or OH;  
     B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR 1 R 1a , —NR 1 COR 1a , —NR 1 CO 2 R 1a , cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —COR 1b  or OR;  
     R is hydrogen, alkyl of 1-6 carbon atoms, —COR 1 , —(CH 2 ) n CO 2 R 1 , —CH(R 1a )CO 2 R 1 , —SO 2 R 1 , —(CH 2 ) m CH(OH)CO 2 R 1 , —(CH 2 ) m COCO 2 R 1 , —(CH 2 ) m CH═CHCO 2 R 1 , or —(CH 2 ) m O(CH 2 )CO 2 R 1 ;  
     R 1  is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH 2 CO 2 R 1 ;  
     R 1′  is hydrogen or alkyl of 1-6 carbon atoms  
     E is S, SO, SO 2 , O, or NR 1c ;  
     X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino, NR 2 R 2a , NR 2 COR 2a , cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —OCH 2 CO 2 R 2b  or —COR 2c ;  
     Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, —OR 3 , SR 3 , NR 3 R 3a , —COR 3b , morpholine or piperidine;  
     R 1a , R 1c , R 2 , R 2a  R 3 , R 3a  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;  
     R 1b  is alkyl of 1-6 carbon atoms or aryl;  
     R 2b  is hydrogen, alkyl of 1-6 carbon atoms;  
     R 2c  and R 3b  are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;  
     C is hydrogen, halogen or OR 4 ;  
     R 4  is hydrogen, alkyl of 1-6 carbon atoms, —CH(R 5 )W, —C(CH 3 ) 2 CO 2 R 6 , 5-thiazolidine-2,4-dione, —CH(R 7 )(CH 2 ) m CO 2 R 6 , —COR 6 , —PO 3 (R 6 ) 2 , —SO 2 R 6 , —(CH 2 ) p CH(OH)CO 2 R 6 , —(CH 2 ) p COCO 2 R 6 , —(CH 2 ) p CH═CHCO 2 R 6 , or —(CH2) p O(CH 2 ) q CO 2 R 6 ;  
     R 5  is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —CH 2 (1H-imidazol-4-yl), —CH 2 (3-1H-indolyl), —CH 2 CH 2 (1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH 2 CH 2 (1-oxo-1,3-dihydro-isoindol-2-yl), —CH 2 (3-pyridyl), —CH 2 CO 2 H, or —(CH 2 ) n G;  
     G is NR 6a R 7a , NR 6a COR 7a ,  
                 
 
     W is CO 2 R 6 , CONH 2 , CONHOH, CN, CONH(CH 2 ) 2 CN, 5-tetrazole, —PO 3 (R 6 ) 2 , —CH 2 OH, —CONR 6b CHR 7b , —CH 2 NR 6b CHR 7b CO 2 R 6 , —CH 2 OCHR 7b CO 2 R 6  —CH 2 Br, or —CONR 6b CHR 7b CO 2 R 6 ;  
     R 6 , R 6a , R 7 , R 7a  are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;  
     R 6b  is hydrogen or —COR 6c ;  
     R 6c  is alkyl of 1-6 carbon atoms or aryl;  
     R 7b  is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;  
     Z 1  and Z 2  are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR 1 R 1a , —NR 1 COR 1a , cycloalkylamino of 3-8 carbon atoms, morpholino, or OR 8 , or Z 1  and Z 2  may be taken together as a diene unit having the formula —CH═CR 9 —CR 10 ═CR 11 —;  
     R 8  is hydrogen, alkyl of 1-6 carbon atoms, or aryl;  
     R 9 , R 10 , and R 11  are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms  
     m is 1 to 4  
     n is 1 or 2;  
     p is 1 to 4;  
     q is 1 to 4;  
     or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/109.813, which was converted from U.S. patentapplication Ser. No. 09/076,712, filed May 12, 1998, pursuant to apetition filed under 37 C.F.R. 1.53(c)(2)(i) on Aug. 17, 1998.

BACKGROUND OF THE INVENTION

[0002] The prevalence of insulin resistance in glucose intolerantsubjects has long been recognized. Reaven et al (American Journal ofMedicine 1976, 60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

[0003] Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

[0004] The association of hyperinsulinemia with obesity and withischemic diseases of the large blood vessels (e.g. atherosclerosis) hasbeen well established by numerous experimental, clinical andepidemiological studies (summarized by Stout, Metabolism 1985, 34, 7,and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987,3, 463). Statistically significant plasma insulin elevations at 1 and 2hours after oral glucose load correlates with an increased risk ofcoronary heart disease.

[0005] Since most of these studies actually excluded diabetic subjects,data relating the risk of atherosclerotic diseases to the diabeticcondition are not as numerous, but point in the same direction as fornondiabetic subjects (Pyorala et al). However, the incidence ofatherosclerotic diseases in morbidity and mortality statistics in thediabetic population exceeds that of the nondiabetic population (Pyoralaet al; Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al,Mortality from diabetes, in Diabetes in America 1985).

[0006] The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

[0007] It is now appreciated that insulin resistance is usually theresult of a defect in the insulin receptor signaling system, at a sitepost binding of insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

[0008] Protein-tyrosine phosphatases (PTPases) play an important role inthe regulation of phosphorylation of proteins. The interaction ofinsulin with its receptor leads to phosphorylation of certain tyrosinemolecules within the receptor protein, thus activating the receptorkinase. PTPases dephosphorylate the activated insulin receptor,attenuating the tyrosine kinase activity. PTPases can also modulatepost-receptor signaling by catalyzing the dephosphorylation of cellularsubstrates of the insulin receptor kinase. The enzymes that appear mostlikely to closely associate with the insulin receptor and therefore,most likely to regulate the insulin receptor kinase activity, includePTP1B, LAR, PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B.J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

[0009] McGuire et al. (Diabetes 1991, 40, 939), demonstrated thatnondiabetic glucose intolerant subjects possessed significantly elevatedlevels of PTPase activity in muscle tissue vs. normal subjects, and thatinsulin infusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

[0010] Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

[0011] The compounds of this invention have been shown to inhibitPTPases derived from rat liver microsomes and human-derived recombinantPTPase-1B (hPTP-1B) in vitro. They are useful in the treatment ofinsulin resistance associated with obesity, glucose intolerance,diabetes mellitus, hypertension and ischemic diseases of the large andsmall blood vessels.

[0012] B. Reidl, et al. (EP 693491A1) disclosed the oxazolodinone A asan antibacterial agent.

[0013] A. Bridges, et al. (EP 568289A2) disclosed thethienothiopheneamidine B as a urokinase inhibitor.

[0014] H. -M. Chen, et al., Indian J. Chem.,Sect. B: Org. Chem. Include.Med. Chem. 1996, 35B(12), 1304-1307 disclosed compound C.

[0015] N. R. Guirguis, et al., J. Prakt. Chem. 1990, 332(3), 414-418disclosed compound D.

[0016] N. R. Guirguis, et al., Liebigs Ann. Chem. 1986, 1003-1011disclosed benzothiophenes E. Also M. C. Dubroeucq et al., (EP 248734A1)dosclosed E (R1═CO₂H) as an anxiolytic.

[0017] T. Kuroda, et al., J. Org. Chem. 1994, 59, 7353-7357 and J. Chem.Soc., Chem. Commun. 1991, 1635-1636 disclosed benzothiophenes F.

[0018] A. I. Hashem, J. Prakt. Chem. 1977, 319, 689-692 disclosedbenzofuran G.

[0019] Y. Akao, et al., Jpn. Kokai Tokkyo Koho JP 04016854 A2(Japanesepatent, CA: 117:36570) disclosed six compounds containing the4-aryl-naphtho[2,3-b]thiophene ring system. These compounds werecyclobutenediylium dimers of that ring, system made aselectrophotographic photoreceptors. One typical example is shown bystructure H below.

[0020] J. P. Konopelski, et al., Synlett 1996, 609-611 disclosed indoleI.

[0021] P. Molina, et al, Tetrahedron, 1994, 50, 5027-36 and TetrahedronLett., 1993, 34, 2809-2812 disclosed indole derivatives J.

[0022] A. Napolitano, et al., Tetrahedron 1989, 45, 6749-60 disclosedindole K.

[0023] G. Dryhurst, et al., J. Am. Chem. Soc. 1989, 111, 719-726disclosed compound L.

[0024] M. d'Ischia, et al., Tetrahedron 1987, 43, 431-434 disclosedcompound M.

DESCRIPTION OF THE INVENTION

[0025] This invention provides a compound of formula I having thestructure

[0026] A is hydrogen, halogen, or OH;

[0027] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a), —NR¹CO₂R^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, —COR^(1b) or OR;

[0028] R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹, —(CH₂)_(n)CO₂R¹,—CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹, —(CH₂)_(m)COCO₂R¹,—(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;

[0029] R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, or CH₂CO₂R^(1′);

[0030] R^(1′) is hydrogen or alkyl of 1-6 carbon atoms

[0031] E is S, SO, SO₂, O, or NR^(1c);

[0032] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy,nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino of 3-8 carbonatoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or—COR^(2c);

[0033] Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkylof 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkylof 6-12 carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine orpiperidine;

[0034] R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0035] R^(1b) is alkyl of 1-6 carbon atoms or aryl;

[0036] R^(2b) is hydrogen, alkyl of 1-6 carbon atoms;

[0037] R^(2c) and R^(3b) are each, independently, alkyl of 1-6 carbonatoms, aryl, or aralkyl of 6-12 carbon atoms;

[0038] C is hydrogen, halogen or OR⁴;

[0039] R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶;

[0040] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G;

[0041] G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

[0042] W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole,—PO₃(R⁶)₂, —CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶,—CH₂OCHR^(7b)CO₂R⁶ —CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶;

[0043] R⁶, R^(6a), R⁷, R^(7a) are each, independently, is hydrogen,alkyl of 1-6 carbon atoms, or aryl;

[0044] R^(6b) is hydrogen or —COR^(6c);

[0045] R^(6c) is alkyl of 1-6 carbon atoms or aryl;

[0046] R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of1-6 carbon atoms;

[0047] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—;

[0048] R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0049] R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

[0050] m is 1 to 4

[0051] n is 1 or 2;

[0052] p is 1 to 4;

[0053] q is 1 to 4;

[0054] or a pharmaceutically acceptable salt thereof, which are usefulin treating metabolic disorders related to insulin resistance orhyperglycemia.

[0055] Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety, such as when R⁵ isCH2(3-pyridyl), or Y is morpholine or contains similar basic moieties.Salts may also be formed from organic and inorganic bases, preferablyalkali metal salts, for example, sodium, lithium, or potassium, when acompound of this invention contains a carboxylate or phenolic moiety.

[0056] Alkyl includes both straight chain as well as branched moieties.Halogen means bromine, chlorine, fluorine, and iodine. It is preferredthat the aryl portion of the aryl or aralkyl substituent is a phenyl ornaphthyl; with phenyl being most preferred. The aryl moiety may beoptionally mono-, di-, or tri- substituted with a substituent selectedfrom the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbonatoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each ofthe alkyl groups is of 1-6 carbon atoms, nitro, cyano, —CO₂H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms.

[0057] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

[0058] The compounds of this invention may be atropisomers by virtue ofpossible restricted or slow rotation about the aryl-tricyclic oraryl-bicyle single bond. This restricted rotation creates additionalchirality and leads to enantiomeric forms. If there is an additionalchiral center in the molecule, diasteriomers exist and can be seen inthe NMR and via other analytical techniques. While shown without respectto atropisomer stereochemistry in Formula I, the present inventionincludes such atoropisomers (enantiomers and diastereomers; as well asthe racemic, resolved, pure diastereomers and mixutures of diasteomers)and pharmaceutically acceptable salts thereof.

[0059] Preferred compounds of this invention include compounds offormula (I), having the structure

[0060] wherein

[0061] A is hydrogen or halogen

[0062] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl,cycloalkyl of 3-8 carbon atoms, nitro or OR;

[0063] R is hydrogen or alkyl of 1-6 carbon atoms;

[0064] E is S, or O;

[0065] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN,perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino,morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;

[0066] R¹, R^(1a), R², R^(2a), R³, and R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0067] Y is hydrogen, halogen, OR³, SR³, NR³R^(3a) or morpholine;

[0068] C is hydrogen, halogen, or OR⁴;

[0069] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₉R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶;

[0070] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl);

[0071] W is CO₂R⁶, —CONH₂, —CONHOH, or 5-tetrazole, or—CONR^(6b)CHR^(7b)CO₂R⁶;

[0072] R⁶, R^(6a), R^(6b),R⁷, R^(7a), and R^(7b) are each,independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0073] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹-CR¹⁰═CH—;

[0074] R⁹ and R¹⁰ are independently, hydrogen, or alkyl of 1-6 carbonatoms;

[0075] p is 1 to 4;

[0076] q is 1 to 4;

[0077] or a pharmaceutically acceptable salt thereof.

[0078] More preferred compounds of this invention include compounds offormula (I), having the structure

[0079] wherein

[0080] A is hydrogen;

[0081] B and D are each, independently, halogen, alkyl of 1-6 carbonatoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8 carbonatoms;

[0082] E is S or O;

[0083] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkylof 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxyof 6-12 carbon atoms, arylsulfanyl;

[0084] Y is hydrogen or —NR¹R², or morpholine;

[0085] R¹ and R² are each, independently, hydrogen or alkyl of 1-6carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

[0086] C is OR⁴;

[0087] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W, or5-thiazolidine-2,4-dione;

[0088] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl);

[0089] W is —CO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, —PO₃(R⁶)₂, or—CONR⁶CHR⁶CO₂R⁶

[0090] R⁶ is hydrogen or alkyl of 1-6 carbon atoms;

[0091] Z¹ and Z² are taken together as a diene unit having the formula—CH═CH—H═CH—;

[0092] or a pharmaceutically acceptable salt thereof.

[0093] Even more preferred compounds of this invention include:

[0094](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0095](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

[0096] (R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionic acid;

[0097](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

[0098] [4-(9-bromo-2,3 -dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-acetic acid;

[0099](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;

[0100](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0101](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0102](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0103](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

[0104](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0105](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0106](S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0107]2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0108](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

[0109][2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;

[0110] 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

[0111]2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

[0112](R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0113](R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid,

[0114](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid,

[0115](R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid,

[0116]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

[0117]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0118] or pharmaceutically acceptable salts thereof.

[0119] The compounds of this invention can be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using to literature procedures.These schemes show the preparation of representative compounds of thisinvention.

[0120] In Scheme 1, 2, 3-dimethylthiophene (II: E is S) is prepared fromcommercially available 3-methyl-thiophene-carboxaldehyde usingWolff-Kishner conditions (hydrazine followed by KOH/ethylene glycolreflux). Compound (II: E is S or O) is treated with one to 1.3 molarequivalents of an alkyl lithium reagent such as N-butyl lithium mostpreferably in a nonprotic solvent such as THF at temperatures rangingfrom −78° C. to room temperature under an inert atmosphere such asnitrogen or argon to provide the 2-lithiated-thiophene or furanderivative. This lithiated analog is reacted in situ with one or moremolar equivalents of benzaldehyde, generally at −78° C. to roomtemperature for 5 min to 3 h to provide the compound of formula (III:Q=OH; E is S or O). The hydroxy group (Q=OH) of (III) can be removed bya number of reduction procedures such as hydrogenation using palladiumcatalysts to produce the compound of formula (III: Q=H; E is S or O) butis most conveniently removed using the method of Nutaitis, et. al. (Org.Prep. and Proceed. Int. 1991, 23, 403-411) in which (III: Q=OH; E is Sor O) is stirred with one to ten molar equivalents of sodium borohydridein a suitable solvent such as ether, THF or dichloromethane at 0° C. toroom temperature and one to fifty molar equivalents of trifluoroaceticacid is slowly added over a 15 min to 3 h period to produce the compoundof formula (III: Q=H; E is S or O). Alternatively, the 2-lithiatedanalog of compound (II: E is S or O) in a nonprotic solvent such as THFcan be reacted with one or more molar equivalents of a benzyl halidesuch as benzyl bromide (PhCH₂Br) at −78° C. to room temperature todirectly provide the compound of formula (III: Q=H; E is S or O).

[0121] The compounds of formula (III: Q=H; E is S or O) can be acylatedwith one or more molar equivalents of a commercially available benzoicacid chloride of formula (IV: A, B, C, D is H or OMe; with the A, B, C,D, combination of substituents having at least one OMe group but notmore than three OMe groups) to produce the acylated derivative offormula (V: A, B, C, D is H or OMe; with the A, B, C, D, combination ofsubstituents having at least one OMe group but not more than three OMegroups; E is S or O). This acylation is accomplished most readily usinga one to five molar equivalents of a Lewis acid catalyst such as tintetrachloride or aluminum chloride in an inert solvent such asdichloromethane, 1, 2-dichloroethane or carbon disulfide, generally attemperatures such as −78° C. to room temperature.

[0122] Cyclization of the compounds of formula (V: A, B, C, D is H orOMe; with the A, B, C, D, combination of substituents having at leastone OMe group but not more than three OMe groups; E is S or O) isgenerally best accomplished using one to ten molar equivalents of astrong Lewis acid such as a trihaloborane, most convenientlytribromoborane. The reaction is best performed at −78° C. with warmingto room temperature or heating to 50° C. in a halocarbon solvent such asdichloromethane under an inert atmosphere such as nitrogen or argon.These procedures not only effect cyclization and aromatization withconcomitant loss of water, but also result in demethylation of anypendant methoxy moieties and result in the production of compounds offormula (Ia: A, B, C, D is H or OH; with the A, B, C, D, combination ofsubstituents having at least one OH group but not more than three OHgroups; E is S or O).

[0123] In an analogous fashion to the reactions above in Scheme 1, thecompounds of formula (Ia: A is H; B, D is alkyl of 1-6 carbon atoms orfluoro; C is OH; E is S or O) can be prepared starting from the compoundof formula (III: Q is H; E is S or O) and the appropriate benzoic acidchloride (IV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C isOMe). The benzoic acid chloride (IV: A is H; B, D is alkyl of 1-6 carbonatoms or fluoro; C is OMe). is prepared from the corresponding benzoicacid by standard procedures using reagents such as oxalyl chloride andthionyl chloride. The starting benzoic acid of the benzoic acid chloride(IV: A is H; B, D is alkyl of 1-6 carbon atoms or fluoro; C is OMe) iscommercially available or can be easily prepared by known procedures.For example, the acid starting material for benzoic acid chloride (IV: Ais H; B, D is isopropyl; C is OMe) can be prepared using a modificationof the method of Schuster, et al., J. Org. Chem. 1988, 53, 5819. Thuscommercially available 2, 6-diisopropyl phenol is brominated in the4-position (bromine/acetic acid), methylated (iodomethane/potassiumcarbonate/DMF), reacted with n-butyl lithium to effect lithium halogenexchange and the resultant organolithium species is reacted with carbondioxide to provide 3, 5-diisopropyl, 4-methoxy benzoic acid.

[0124] Further derivatives of the compounds of formula (I) in Scheme 2can be prepared by the following methods. The phenol of formula (Ib: B,D, X is H; C is OH; E is S or O) (Scheme 2) can be convenientlyiodinated to the diiodophenol of formula (Ib: B, D is I; X is H; C isOH; E is S or O) using at least two molar equivalents of iodine in -thepresence of two or more molar equivalents of an alkali metal hydroxidesuch as NaOH in a alcohol solvent such as methanol at −20° C. to roomtemperature. Similarly the monoiodophenol (Ib: B is I; X, D is H; C isOH; E is S or O) can be prepared from the phenol of formula (Ib: B, D, Xis H; C is OH; E is S or O) (Scheme 2) using one to 1.5 molarequivalents of iodine in the presence of at least one equivalent of analkali metal hydroxide such as NaOH in a alcohol solvent such asmethanol at −20° C. to room temperature. Either the monoiodophenol (Ib:B is I; X, D is H; C is OH; E is S or O) or the diiodophenol (Ib: B, Dis I; X is H; C is OH; E is S or O) can be converted to the respectivemethyl ether derivatives of formula (Ib: B is I; X, D is H; C is OMe; Eis S or O) or (Ib: B, D is I; X is H; C is OMe; E is S or O) by reactingthe phenol moiety with a suitable methylating agent such as one or moremolar equivalents of methyl iodide or dimethylsulfate employing a basesuch an alkali methyl carbonate or hydroxide such as potassium carbonateor sodium hydroxide in a suitable solvent such as THF, DMF or DMSO. Thereaction is generally performed at temperatures ranging from 0° C. to60° C.

[0125] The monoiodo methylether derivative of formula (Ib: B is I; X, Dis H; C is OMe; E is S or O) or the diiodo methylether of formula (Ib:B, D is I; X is H; C is OMe; E is S or O) can be reacted with one ormore molar equivalents of copper (I) cyanide for the monoiodo analog ortwo or more molar equivalents of copper (I) cyanide for the diiododerivative to produce the monocyanomethyl ether of formula (Ib: B is CN;X, D is H; C is OMe; E is S or O) or the dicyanomethyl ether of formula(Ib: B, D is CN; X is H; C is OMe; E is S or O). The cyanation reactionis generally performed at temperatures ranging from 100° C. to 250° C.employing polar aprotic solvents such as DMF, 1-methyl-2-pyrrolidinoneor HMPA. Quinoline or pyridine can also be used. The mono or dicyanomethoxy analogs of formula (Ib: B is CN; D is H or CN; X is H; C is OMe;E is S or O); can be converted to the corresponding mono or dicyanophenol analogs of formula (Ic: B is CN; D is H or CN; X is H; E is S orO) (Scheme 2) using standard demethylation procedures including one ormore molar equivalents of boron tribromide or boron trichloride indichloromethane at −78° C. to room temperature; excess neat pyridiniumhydrochloride at 190 to 280° C.; hydrobromic acid in acetic acid at 0°C. to 50° C.; excess trimethylsilylbromide or trimethylsilyliodide indichloromethane, carbon tetrachloride or acetonitrile at −78° C. to 50°C.; lithium iodide in pyridine or quinoline at temperatures from 100° to250° C. and one or more molar equivalents of ethyl, methyl or isopropylmercaptan in the presence of one or more molar equivalents of a Lewisacid such as aluminum trichloride or boron trifluoride in a solvent suchas dichloromethane at temperatures ranging from −78° C. to 50° C.

[0126] The monoiodo methylether derivative of formula (Ib: B is I; X, Dis H; C is OMe; E is S or O) or the diiodo methylether of formula (Ib:B, D is I; X is H; C is OMe; E is S or O) (Scheme 2) can be reacted withone or more molar equivalents of copper (I) bromide for the monoiodoanalog or two or more molar equivalents of copper (I) bromide for thediiodo derivative to produce the monobromo methyl ether of formula (Ib:B is Br; X, D is H; C is OMe; E is S or O) or the dibromo-methyl etherof formula (Ib: B, D is Br; X is H; C is OMe; E is S or O). Thebromine/idodine exchange reaction is generally performed at temperaturesranging from 100° C. to 250° C. employing polar aprotic solvents such asDMF, 1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also beused. The mono or dibromo methoxy analogs of formula (Ib: B is Br; D isH or Br X is H; C is OMe; E is S or O) can be converted to thecorresponding mono or dibromo phenol analogs of formula (Ic: B is Br; Dis H or Br; X is H; E is S or O) (Scheme 2) using standard demethylationprocedures including one or more molar equivalents of boron tribromideor boron trichloride in dichloromethane at −78° C. to room temperature;excess neat pyridinium hydrochloride at 190 to 280° C.; hydrobromic acidin acetic acid at 0° C. to 50° C.; excess trimethylsilylbromide ortrimethylsilyliodide in dichloromethane, carbon tetrachloride oracetonitrile at −78° C. to 50° C.; lithium iodide in pyridine orquinoline at temperatures from 100° to 250° C. and one or more molarequivalents of ethyl, methyl or isopropyl mercaptan in the presence ofone or more molar equivalents of a Lewis acid such as aluminumtrichloride or boron trifluoride in a solvent such as dichloromethane attemperatures ranging from −78° C. to 50° C.

[0127] Further derivatives of the compounds of formula (I) in Scheme 3can be prepared by the following methods. The compounds of formula (Id:B, C, D is H or OH; with the B. C, D combination having at least one OHgroup; E is S or O) (Scheme 3) can be acylated on the phenolic oxygenusing one or more molar equivalents of suitable acylating agent toprovide the compounds of formula (Id: B, C, D is H or OCOR; with the B,C, D combination having at least one OCOR group; R is alkyl of 1-6carbon atoms, aryl; E is S or O). The acylating agent is generally alkylof 1-6 carbon atoms or aryl carboxylic acid anhydride or alkyl of 1-6carbon atoms or aryl carboxylic acid chloride. The reaction is run understandard conditions, for example the use of pyridine as solvent with orwithout a co-solvent such as dichloromethane at 0° C. to roomtemperature. The acylated phenols of formula (Id: B, C, D is H or OCOR;with the B, C, D combination having at least one OCOR group; R is alkylof 1-6 carbon atoms, aryl; E is S or O) can then be brominated in the9-position of the naphtho[2,3-b]thiophene or the naphtho[2,3-b]furanring to form the acylated bromophenols of formula (Ie: B, C, D is H orOCOR; with the B, C, D combination having at least one OCOR group; R isalkyl of 1-6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3). Thisbromination reaction is generally done using 1 to 1.3 molar equivalentsof molecular bromine in the dark with a catalytic amount of iron (III)chloride in an inert solvent such as dichloromethane or carbontetrachloride at temperatures ranging from −78° C. to room temperature.

[0128] Using a similar bromination reaction, the phenols of formula (Id:B, D is alkyl of 1-6 carbon atoms, C is OH; E is S or O) can then bebrominated in the 9-position of the naphtho[2,3-b]thiophene hene or thenaphtho[2,3-b]furan ring to form the bromophenols of formula (Ie: B, Dis alkyl of 1-6 carbon atoms, C is OH; X is Br; E is S or O) (Scheme 3).This bromination reaction is generally done using 1 to 1.3 molarequivalents of molecular bromine in the dark with a catalytic amount ofiron (III) chloride in an inert solvent such as dichloromethane orcarbon tetrachloride at temperatures ranging from −78° C. to roomtemperature.

[0129] The acyl group can then be removed from the acylated bromophenolsof formula (Ie: B, C, D is H or OCOR; with the B, C, D combinationhaving at least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; Xis Br; E is S or O) to provide the bromophenols of formula (Ie: B, C, Dis H or OH; with the B, C, D combination having at least one OH group; Xis Br; E is S or O) (Scheme 3) using standard conditions. Theseconditions include aqueous base in which one or more molar equivalentsof alkali metal hydroxide such as sodium hydroxide is used in water witha co-solvent such as THF, dioxane or a 1-6 carbon alcohol such asmethanol or mixtures of THF and a 1-6 carbon atom alcohol attemperatures ranging from 0° C. to 40° C. Acid conditions may also beemployed in which the compound is reacted with one or more molarequivalents of a mineral acid such as HCl or sulfuric acid in water withor without a co-solvent such as THF at temperatures ranging from roomtemperature to 80° C.

[0130] The acylated phenols of formula (Id: B, C, D is H or OCOR; withthe B, C, D combination having at least one OCOR group; R is alkyl of1-6 carbon atoms, aryl; E is S or O) can be nitrated to provide thenitro compounds of formula (Ie: B, C, D is H or OCOR; with the B, C,,Dcombination having at least one OCOR group; R is alkyl of 1-6 carbonatoms, aryl; X is NO₂; E is S or O) (Scheme 3). Dilute nitric acid attemperatures ranging from 0° C. to room temperature is suitable toeffect this transformation. The nitro compounds of formula (Ie: B, C, Dis H or OCOR; C, D cannot both be H; R is alkyl fo 1-6 carbon atoms,aryl; X is NO₂; E is S or O) can be further reduced to the primary amineof formula (1e: B, C, D is H or OCOR; with the B, C, D combinationhaving at least one OCOR group; R is alkyl fo 1-6 carbon atoms, aryl; Xis NH₂; E is S or O) using a suitable reducing agent such as catalytichydrogenation with a palladium or platinum catalyst, tin dichloride inaqueous HCl or in ethyl acetate. The acyl group of the compounds offormula (Ie: B, C, D is H or OCOR; with the B, C, D combination havingat least one OCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is NO₂or NH₂; E is S or O) can be removed using standard conditions.

[0131] The acylated bromophenols of formula (Ie: B, C, D is H or OCOR;with the B, C, D combination having at least one OCOR group; R is alkylof 1-6 carbon atoms, aryl; X is Br; E is S or O) (Scheme 3) can beconverted to the acylated cyanophenols of formula (Ie: B, C, D is H orOCOR; with the B, C, D combination having at least one OCOR group; R isalkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O) by reaction withone or more molar equivalents of copper (I) cyanide. The cyanationreaction is generally performed at temperatures ranging from 100° C. to250° C. employing polar aprotic solvents such as DMF,1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also beused. Often the acyl group of (Ie: B, C, D is H or OCOR; with the B, C,D combination having at least one OCOR group; R is alkyl of 1-6 carbonatoms, aryl; X is CN; E is S or O) is liberated under the cyanationreaction conditions to afford the cyanophenols of formula (Ie: B, C, Dis H or OH; with the B, C, D combination having at least one OH group; Xis CN; E is S or O). This liberation of the acyl group to afford thecyanophenols of formula (Ie: B, C, D is H or OH; with the B, C, Dcombination having at least one OH group; X is CN; E is S or O) can beeffected most readily by addition of one or more molar equivalents ofalkali metal hydroxide in water to the reaction mixture containing (Ie:B, C, D is H or OCOR; with the B, C, D combination having at least oneOCOR group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E is S or O)prior to workup. The acyl group can also be removed from the isolatedacylated cyanophenols of formula (Ie: B, C, D is H or OCOR; with the B,C, D combination having at least one OCOR group; R is alkyl of 1-6carbon atoms, aryl; X is CN; E is S or O) to provide the cyanophenols offormula (Ie: B, C, D is H or OH; with the B, C, D combination having atleast one OH group; R is alkyl of 1-6 carbon atoms, aryl; X is CN; E isS or O) using standard conditions. These conditions include aqueous basein which one or more molar equivalents of alkali metal hydroxide such assodium hydroxide is used in water with a co-solvent such as THF, dioxaneor a lower alcohol such as methanol or mixtures of THF and a loweralcohol at temperatures ranging from 0° C. to 40° C. Acid conditions mayalso be employed in which the compound is reacted with one or more molarequivalents of a mineral acid such as HCl or sulfuric acid in water withor without a co-solvent such as THF at temperatures ranging from roomtemperature to 80° C.

[0132] The compounds of formula (Id: B, C, D is H or OH; with the B, C,D combination having at least one OH group; E is S or O) (Scheme 3) canbe sulfonylated on the phenolic oxygen using one or more molarequivalents of suitable sulfonylating agent to provide the sulfonic acidesters of formula (Id: B, C, D is H or OSO₂R; with the B, C, Dcombination having at least one OSO₂R group; R is alkyl of 1-6 carbonatoms, aryl; E is S or O). The sulfonylating agent is generally a alkylof 1-6 carbon atoms or aryl sulfonic acid anhydride or a alkyl of 1-6carbon atoms or aryl sulfonic acid chloride. The reaction is run understandard conditions such as using pyridine as solvent with or without aco-solvent such as dichloromethane at 0° C. to room temperature.

[0133] The sulfonic acid esters of formula (Id: B, C, D is H or OSO₂R;with the B, C, D combination having at least one OSO₂R group; R is alkylof 1-6 carbon atoms, aryl; E is S or O) can be treated with iodinatingreagents to effect iodination at the 9-position of thenaphtho[2,3-d]thiophene or the naphtho[2,3-d]furan ring to afford theiodo sulfonic acid esters of formula (Ie: B, C, D is H or OSO2R; withthe B, C, D combination having at least one OSO₂R group; R is alkyl of1-6 carbon atoms, aryl; X is I; E is S or O). A suitable iodinatingreagent includes a mixture of 0.7 or more molar equivalents of moleculariodine and 0.25 or more molar equivalents of iodic acid in a mixture ofTHF and 80% aqueous acetic acid with a small amount of concentratedsulfuric acid at temperatures ranging from room temperature to 80° C.The sulfonic ester group can then be removed from the iodo-sulfonic acidesters of formula (Ie: B, C, D is H or OSO₂R; with the B, C, Dcombination having at least one OSO₂R group; R is alkyl of 1-6 carbonatoms, aryl; X is I; E is S or O) to provide the iodophenols of formula(Ie: B, C, D is H or OH; with the B, C, D combination having at leastone OH group; X is I; E is S or O) (Scheme 3) using standard conditions.These conditions include aqueous base in which one or more molarequivalents of alkali metal hydroxide such as sodium hydroxide is usedin water with a co-solvent such as THF, dioxane or a lower alcohol suchas methanol or mixtures of THF and a lower alcohol at temperaturesranging from room temperature to 110° C.

[0134] The iodo sulfonic acid esters of formula (If: C, D is H or OSO₂R;C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl) ; E is S orO are a convenient starting point for further derivatives of thecompounds of formula (I) as shown in Scheme 4 and the methods below. Thecompounds (If: C, D is H or OSO R; C, D cannot both be H; R is alkyl of1-6 carbon atoms, aryl; E is S or O) can be reacted with a reagent thatcatalyzes the exchange of the iodine atom in (If) with a lowerperfluoroalkyl group to afford the compound of formula (Ig: C, D is H orOSO₂R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X islower perfluoroalkyl; E is S or O) (Scheme 4). The reagent andconditions to effect this exchange include reacting (If) under anhydrousconditions with one to ten molar equivalents of a sodiumperfluorocarboxylate (RCO₂Na: R is perfluoroalkyl) and one to five molarequivalents of copper (I) iodide in a high boiling inert solvent such asDMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140°C. to 200° C. Alternatively, the compound of formula (Ig: C, D is H orOSO₂R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X islower perfluoroalkyl; E is S or O) can be prepared from the compound offormula (If: C, D is H or OSO₂R; C, D cannot both be H; R is alkyl of1-6 carbon atoms, aryl; E is S or O) by reacting the former with one toten molar molar equivalents of a perfluoroalkyl iodide and one to fivemolar molar equivalents of activated Cu⁰ in a high boiling inert solventsuch as DMF, DMA or 1-methyl-2-pyrrolidinone at temperatures rangingfrom 140° C. to 200° C. Still, alternatively, the compound of formula(If: C, D is H or OSO₂R; C, D cannot both be H; R is alkyl of 1-6 carbonatoms, aryl; E is S or O) can be reacted with 0.5 to two molarequivalents of bis(trifluoromethyl)mercury and two to four molarequivalents of activated Cu⁰ in a high boiling inert solvent such asDMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 140°C. to 200° C. to produce the compound of (Ig: C, D is H or OSO₂R; C, Dcannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X is CF₃; E is Sor O).

[0135] 9-alkyl derivatives of the compound of formula (Ig: C, D is H orOSO₂R; C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; X isalkyl of 1-6 carbon atoms; E is S or O) (Scheme 4) can be prepared byreaction of (If: C, D is H or OSO₂R; C, D cannot both be H; R is alkylof 1-6 carbon atoms, aryl; E is S or O) with three or more molarequivalents of lower tetra-alkyltin in the presence of a palladiumcatalyst such as 1 to 10 mole % of bis(triphenylphosphine)palladium IIchloride in a suitable solvent such as DMF, DMA or1-methyl-2-pyrrolidinone at temperatures ranging from 140° C. to 200° C.

[0136] The sulfonic ester group can then be removed from the sulfonicacid esters of formula (Ig: C, D is H or OSO₂R; C, D cannot both be H; Ris alkyl of 1-6 carbon atoms, aryl; X is alkyl of 1-6 carbon atoms orlower perfluoroalkyl; E is S or O) to provide the phenols of formula(Ig: C, D is H or OH; C, D cannot both be H; X is alkyl of 1-6 carbonatoms or lower perfluoroalkyl; E is S or O) using standard conditions.These conditions include aqueous base in which one or more molarequivalents of alkali metal hydroxide such as sodium hydroxide is usedin water with a co-solvent such as HF, dioxane or a lower alcohol suchas methanol or mixtures of THF and a lower alcohol at temperaturesranging from room temperature to 110° C.

[0137] 9-Alkoxy derivatives of the compound of formula (Ig: C, D is H,OH; C, D cannot both be H; X is alkoxy of 1-6 carbon atoms; E is S or O)can be prepared by reaction of (If: C, D is H or OSO₂R; C, D cannot bothbe H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O) with three ormore molar equivalents of lower alkali metal alkoxide such as sodiummethoxide in the presence of a copper (I) or copper (II) catalyst suchas 1 to 10 mole % copper (II) chloride in a suitable solvent such asDMF, DMA or 1-methyl-2-pyrrolidinone at temperatures ranging from 80° C.to 180° C. Under the reaction conditions, the sulfonic acid group offormula (If: C, D is H or OSO₂R; C, D cannot both be H; R is alkyl of1-6 carbon atoms, aryl; E is S or O) is removed.

[0138] 9-Sulfanyl derivatives of the compound of formula (Ig: C, D is Hor OH; C, D cannot both be H; X is alkyl of 1-6 carbon atomssulfanyl,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is Sor O) can be prepared by reaction of formula (If: C, D is H or OSO₂R; C,D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S or O)with one or more molar equivalents of the appropriate alkyl of 1-6carbon atomsthiol, arylthiol, thiopyridine or2-N,N-dimethylaminoethyl-mercaptan, one or more molar equivalents of analkali metal hydroxide such as sodium hydroxide, one or more molarequivalents of a copper (I) or copper (II) catalyst such as copper (I)oxide in a suitable solvent such as DMF, DMA or 1-methyl-2-pyrrolidinoneat temperatures ranging from 100° C. to 180° C. Under the reactionconditions, the sulfonic acid group of formula (If: C, D is H or OSO₂R;C, D cannot both be H; R is alkyl of 1-6 carbon atoms, aryl; E is S orO) is removed.

[0139] Further derivatives of the compounds of formula (I) in Scheme 5can be prepared by the following methods. The phenols of formula (Ih: Ais H or OH; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be brominated in twopositions to afford the dibromphenols of formula (Ii: A is H or OH; B, Dis Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molarequivalents of molecular bromine in an appropriate solvent such asacetic acid. One to fifty molar equivalents of a salt of acetic acidsuch as potassium or sodium acetate can also be used as a co-reagent inthis reaction although it is not absolutely required.

[0140] The phenols of formula (Ih: A is H; X is H, halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O) can bemononitrated to the phenols of formula (Ii: A is H; B is NO₂; D is H; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;E is S or O) most conveniently using iron (III) trinitrate in a loweralcohol solvent.

[0141] The nitro compounds of formula (Ii: A is H; B is NO₂; D is H; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;E is S or O) can be reduced to the amino compounds of formula (Ii: A isH; B is NH₂; D is H; X is H, halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; E is S or O) most readily using tindichloride in ethylacetate at 40 to 100° C. or with hydrazine andMontmorillinite clay in ethanol at 40 to 100° C.

[0142] The nitro compounds of formula (Ii: A is H; B is NO₂; D is H; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;E is S or O) can also be brominated to the compounds of formula (Ii: Ais H; B is NO₂; D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molarequivalents of molecular bromine in an appropriate solvent such asacetic acid. One to fifty molar equivalents of a salt of acetic acidsuch as potassium or sodium acetate can also be used as a co-reagent inthis reaction although it is not absolutely required. The bromo nitrocompounds of formula (Ii: A is H; B is NO₂; D is Br; X is H, halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is Sor O) can be reduced to the bromo amino compounds of formula (Ii: A isH; B is NH,; D is Br; X is H, halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) most readily using tindichloride in ethylacetate at 40 to 100° C. or with hydrazine andMontmorillinite clay in ethanol at 40 to 100° C.

[0143] The amino compounds of formula (Ii: A is H; B is NH₂; D is H orBr; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, amino,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be acylated with oneor more equivalents of a suitable acylating agent of formula(LG)COR^(1a) or (LG)CO₂R^(1a) (wherein LG is a leaving group such as Clfor an acyl halide or chloroformate or OCOR^(1a) or OCO₂R^(1a) for ananhydride or mixed anyhdride, etc.; R^(1a) is alkyl of 1-6 carbon atoms,aralkyl and aryl) to produce the compounds of formula (Ii: A is H; B isNHCOR^(1a) or NHCO₂R^(1a); D is H or Br; X is H, halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, amino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is S or O; R^(1a)is . R^(1a) is alkyl of 1-6 carbon atoms aralkyl and aryl). Theseacylations can be performed in the presence of one or more equivlents ofa suitable base such as an alkali metal hydroxide, carbonate orbicarbonate or an organic amine base such as triethylamine or pyridineand with or without a suitable solvent such a chloroform,dichloromethane, THF, dioxane and water or mixtures of these solventsand with or without the presence of a catalyst such as 4-N,N-dimethylpyridine.

[0144] The dibromo-bisphenols of formula (Ii: A is OH; B, D is Br; X isH; E is S or O) can be further brominated in the 9-position of thenaphtho[2,3-b]thiophene or the naphtho[2,3-b]furan ring to form thebisphenols of formula (Ii: A is OH; B, D, X is Br; E is S or O). Thisbromination reaction is generally done using 1 to 1.3 molar equivalentsof molecular bromine in the dark with a catalytic amount of iron (III)chloride in an inert solvent such as dichloromethane or carbontetrachloride at temperatures ranging from −78° C. to room temperature.

[0145] Further derivatives of the compounds of formula (I) in Scheme 6can be prepared by the following methods. The phenols of formula (Ij: Cis H; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be monobrominated toprovide the provide the bromophenols of formula (Ik: A, B is H; C is Br;D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; E is S or O) using at least 1 molarequivalent of molecular bromine in an appropriate solvent such as aceticacid or dibrominated to provide the bromophenols of formula (Ik: B is H;A, C is Br; D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) using at least 2 molarequivalents of molecular bromine in an appropriate solvent such asacetic acid. Similarly, the bisphenols of formula (Ij: C, D is OH; X ishalogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; E is Sor O) can be monobrominated to provide a mixture of the bromobisphenolsof formula (Ik: A is H; B is Br; C, D is OH; X is halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; E is S or O) and(Ik: A is Br; B is H; C, D is OH; X is halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; E is S or O) using at least 1 molarequivalents of molecular bromine in an appropriate solvent such asacetic acid. This mixture can be separated into pure monobromo productsby conventional means.

[0146] Further derivatives of the compounds of formula (I) in Scheme 7can be prepared by the following methods. The phenols of formula (Il: Bis H; A, C is H or Br; D is OH; X is halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be alkylated with oneor more molar equivalents of an alkyl haloacetate of formula(X²CHR^(6a)CO₂R⁶ where X² is Cl, Br or I and R⁶ is alkyl of 1-6 carbonatoms, R^(6a) is H) and with one or more molar equivalents of an alkalimetal carbonate such as potassium carbonate in a polar aprotic solventsuch as DMF to afford the alkylated product of formula (Im: B is H; A, Cis H or Br; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; R⁶ is alkyl of 1-6 carbon atoms,R^(6a) is H; E is S or O).

[0147] Alternatively the bisphenols of formula (Il: A, B is H or Br; C,D is OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be diaklylated withtwo or more molar equivalents of an alkyl haloacetate of formula(X²CHR^(6a)CO₂R⁶ where X² is Cl, Br or I and R⁶ is alkyl of 1-6 carbonatoms, R^(6a) is H) and with two or more molar equivalents of an alkalimetal carbonate such as potassium carbonate in a polar aprotic solventsuch as DMF to afford the dialkylated esters of formula (Im: A, B is Hor Br; C is OCH₂CO₂R⁶; X is halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; R⁶ is alkyl of 1-6 carbon atoms,R^(6a) is H; E is S or O).

[0148] Still alternatively, the phenols of formula (Il: B is H orhalogen; A is H or halogen; C is H, Br or alkoxy of 1-6 carbon atoms; Dis OH; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; E is S or O) can be reacted with a2-hydroxy carboxylic acid ester of formula CH(OH)(R^(6a))CO₂R⁶ (R⁶,R^(6a) is alkyl of 1-6 carbon atoms, aralkyl, aryl) to afford the estersof formula (Im: B is H or halogen; A is H or halogen; C is H, Br oralkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; R⁶, R^(6a) is alkyl of 1-6 carbonatoms, aralkyl, aryl; E is S or O) under the conditions of the MitsunobuReactions (for a review see Oyo Mitsunobu Synthesis. 1981, 1-27). Theother co-reagents necessary to effect the Mitsunobu Reaction include oneor more molar equivalents of a alkyl of 1-6 carbon atomsazodicarboxylate diester such as diethyl azodicarboxylate or diisopropylazodicarboxylate and one or more molar equivalents of triarylphosphinesuch as triphenylphosphine in a suitable solvent such as diethyl ether,THF, benzene or toluene at temperatures ranging from −20° C. to 120° C.

[0149] The monoesters of formula (Im: A, B is H or halogen; C is H, Bror alkoxy of 1-6 carbon atoms; X is halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; R⁶, R^(6a) is alkyl of 1-6 carbonatoms, aralkyl, aryl; E is S or O) as well as the diesters of formula(Im: A, B is H or Br; C is OCH₂CO₂R⁶, X is halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; R⁶ is alkyl of 1-6 carbon atoms,R^(6a) is H; E is S or O) can be transformed into their carboxylic acidanalogs using standard conditions to afford the moncarboxylic acids offormula (Im: A, B is H or halogen; C is H, Br or alkoxy of 1-6 carbonatoms; X is halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; R⁶ is H; R⁶, is alkyl of 1-6 carbonatoms, aralkyl, aryl; E is S or O) and the dicarboxylic acids of formula(Im: A, B is H or Br; C is OCH₂CO₂H, X is halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; R⁶, R^(6a) is H; E is S or O). Theconditions to effect these transformations include aqueous base in whichone or more molar equivalents of alkali metal hydroxide such as sodiumhydroxide is used in water with a co-solvent such as THF, dioxane or alower alcohol such as methanol or mixtures of THF and a lower alcohol attemperatures ranging from 0° C. to 40° C.

[0150] Further derivatives of the compounds of formula (I) in Scheme 8can be prepared by the following methods. The acetates of formula (In: Xis halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxyof 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H;E is S or O) can be reacted with a halogenating agent, specifically onethat causes benzylic type bromination or chlorination such as one ormore molar equivalents of N-bromosuccinimide, N-chlorosuccinimide orsulfuryl chloride to provide the halo acetates of formula (In: X ishalogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y isCl, Br; E is S or O). This reaction is conveniently done in a suitablesolvent such as dichloromethane or carbontetrachloride at temperaturesranging from 0° C. to room temperature.

[0151] The halo acetates of formula (In: X is halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br; E is Sor O) can be reacted with one or more equivalents of nucleophiles suchas alkoxides (MOR¹), sulfides (MSR¹) or amines (NHR¹R²) (wherein M is aalkali metal such as Na, Li or K; R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl) in a suitable solvent such as THF, DMF ordichloromethane to provide the compounds of formula (In: X is halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y isOR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O). During reaction of the compounds of formula (In:X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;Y is Cl, Br; E is S or O) with nucleophiles there can be concomitentloss of the acetyl group to afford the compounds of formula (Io: B, D isH; X is halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;Y is OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, arylor aralkyl; E is S or O).

[0152] The compounds of formula (In: X is halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; Y is OR¹, SR¹, NR¹R², where R¹, R² isH, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O) can bedeacylated to produce the compounds of formula (Io: B, D is H; X-ishalogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y isCl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms,aryl or aralkyl; E is S or O). The deacylation conditions includeaqueous base in which one or more molar equivalents of alkali metalhydroxide such as sodium hydroxide is used in water with a co-solventsuch as THF, dioxane or a lower alcohol such as methanol or mixtures ofTHF and a lower alcohol at temperatures ranging from 0° C. to 40° C.Acid conditions may also be employed in which the compound is reactedwith one or more molar equivalents of a mineral acid such as HCl orsulfuric acid in water with or without a co-solvent such as THF attemperatures ranging from room temperature to 80° C.

[0153] The compounds of formula (Io: B, D is H; X is halogen, alkyl of1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br, OR¹,SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O) can be brominated in two positions to afford thedibromphenols of formula (Io: B, D is Br; X is halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is Cl, Br, OR¹,SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O) using at least 2 molar equivalents of molecularbromine in an appropriate solvent such as acetic acid. One to fiftymolar equivalents of a salt of acetic acid such as potassium or sodiumacetate can also be used as a co-reagent in this reaction although it isnot absolutely required.

[0154] Further derivatives of the compounds of formula (I) in Scheme 9can be prepared by the following methods. The phenols of formula (Ip: B,D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;Y is H, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; E is S or O) can be alkylated with one or moremolar equivalents of an alkyl haloacetate of formula (X²CH₂CO₂R⁶ whereX² is Cl, Br or I and R⁶ is alkyl of 1-6 carbon atoms) and with one ormore molar equivalents of an alkali metal carbonate such as potassiumcarbonate in a polar aprotic solvent such as DMF to afford the alkylatedproduct of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbonatoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms., aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCO₂R⁶; R⁵is H; R⁶ is alkyl of 1-6 carbon atoms; E is S or O).

[0155] The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be reacted with a 2-hydroxy carboxylic acid ester of formulaCH(OH)(R⁵)CO₂R⁶ (R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), CH₂CO₂R⁶, R⁶ isalkyl of 1-6 carbon atoms) to afford the esters of formula (Iq: B, D isH, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is CO₂R⁶; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3- 1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), CH₂CO₂R⁶, R⁶ isalkyl of 1-6 carbon atoms; E is S or O) under the conditions of theMitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis. 1981,1-27). The other co-reagents necessary to effect the Mitsunobu Reactioninclude one or more molar equivalents of a alkyl of 1-6 carbon atomsazodicarboxylate diester such as diethyl azodicarboxylate or diisopropylazodicarboxylate and one or more molar equivalents of triarylphosphinesuch as triphenylphosphine in a suitable solvent such as diethyl ether,THF, benzene or toluene at temperatures ranging from −20° C. to 120° C.

[0156] The 2-hydroxy carboxylic acid ester of formula CH(OH)(R⁵)CO₂R⁶(R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), CH₂CO₂R⁶, R⁶ isalkyl of 1-6 carbon atoms) are commercially available or can be preparedfrom commercially available carboxylic acid precursors under standardesterification conditions.(S)-(+)-2-Hydroxy-1-oxo-3-dihydro-2-isoindolinebutyric acid, methylester can be prepared from(S)-(+)-2-hydroxy-1,3-dioxo-2-isoindolinebutyric acid, methyl ester viasequential treatment with 1) sodium borohydride in THF-water; 2)trifluoroacetic acid/chloroform; 3) triethylsilane/trifluoroacetic acidand 4) aqueous sodium bicarbonate. 3-(Pyridin-3-yl)-phenyllactic acid,ethyl ester can be prepared according to the two step procedure of B. A.Lefker, W. A. Hada, P. J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208,from commericially available 3-pyridinecarboxaldehyde and ethylchloroacetate.

[0157] The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCO₂tBu; R⁵ is H; E is S or O) can be treated with one or more molarequivalents of a strong base such as lithium diisopropyl amide in asuitable solvent such as THF at temperatures ranging from −78° C. toroom temperature. This procedure produces an anion alpha to the estercarbonyl. The resultant anion is treated with one or more molarequivalents of an alkyl halide of formula X²R⁵ (where X² is halogen; R⁵is alkyl and aralkyl) and warmed to room temperature to produce thealkylated ester of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCO₂tBu; R⁵ is alkyl and aralkyl; E is S or O).

[0158] The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCO₂R⁶; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), CH₂CO₂R⁶, R⁶ is alkylof 1-6 carbon atoms; E is S or O) can be transformed into theircarboxylic acid analogs using standard conditions to afford thecarboxylic acids of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCO₂H; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), CH₂CO₂H; E is Sor O). The conditions to effect these transformations include aqueousbase in which one or more molar equivalents of alkali metal hydroxidesuch as sodium hydroxide is used in water with a co-solvent such as THF,dioxane or a lower alcohol such as methanol or mixtures of THF and alower alcohol at temperatures ranging from 0° C. to 40° C.Alternatively, acid conditions may also be employed in which the abovedmentioned carboxylic acid ester of formula (Iq) is reacted with one ormore molar equivalents of a mineral acid such as HCl or sulfuric acid inwater with or without a co-solvent such as THF at temperatures rangingfrom room temperature to 80° C. Still alternatively, many otherconditions may be employed to effect the above mentioned ester to acidtransformation leading to (Iq). These include reacting the carboxylicacid ester of formula (Iq) with one or more molar equivalents of borontribromide or boron trichloride in dichloromethane at −78° C. to roomtemperature; one or more molar equivalents hydrobromic acid in aceticacid at 0° C. to 50° C.; one or more molar equivalentstrimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbontetrachloride or acetonitrile at −78° C. to 50° C.; one or more molarequivalents lithium iodide in pyridine or quinoline at temperatures from100° to 250° C.

[0159] The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be alkylated with one or more molar equivalents of diethyltrifluoromethylsulfonyloxymethylphosphanate (D. P. Phillion and S. S.Andrew Tet. Lett. 1986, 1477-1480) and with one or more molarequivalents of an alkali metal hydride such as sodium hydride in asuitable solvent such as THF or DMF to afford the diethylphosphonateproduct of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbonatoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isPO₃Et₂; R⁵ is H; R⁶ is alkyl of 1-6 carbon atoms; E is S or O).

[0160] The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be reacted with a 2-hydroxy phosphonic acid diester of formulaCH(OH)(R⁵)PO₃(R⁶)₂, (R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,R⁶ is alkyl of 1-6 carbon atoms) to afford the phosphonic acid diestersof formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isPO₃(R⁶)₂; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R⁶ is alkylof 1-6 carbon atoms; E is S or O) under the conditions of the MitsunobuReactions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27). Theother co-reagents necessary to effect the Mitsunobu Reaction include oneor more molar equivalents of a alkyl of 1-6 carbon atomsazodicarboxylate diester such as diethyl azodicarboxylate or diisopropylazodicarboxylate and one or more molar equivalents of triarylphosphinesuch as triphenylphosphine in a suitable solvent such as diethyl ether,THF, benzene or toluene at temperatures ranging from −20° C. to 120° C.

[0161] The 2-hydroxy phosphonic acid diester of formula CH(OH)(R⁵)PO₃R⁶(R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl, R⁶ is alkyl of 1-6carbon atoms) can be prepared by reacting a dialklylphosphonate offormula HP(O)(OR⁶)₂ (R⁶ is alkyl of 1-6 carbon atoms) with an aldehydeof formula R⁵CHO (R⁵ is alkyl of 1-6 carbon atoms, aryl, aralkyl) understandard conditions.

[0162] The phosphonic acid diesters of formula (Iq: B, D is H, halogen,CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is PO₃(R⁶)₂; R⁵ is H, alkyl of 1-6 carbonatoms, aralkyl, aryl, R⁶ is alkyl of 1-6 carbon atoms; E is S or O) canbe transformed into their phosphonic acid analogs using standardconditions to afford the phosphonic acids of formula (Iq: B, D is H,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is PO₃H₂; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, R⁶ is H, alkyl of 1-6 carbon atoms; E is S or O). Theconditions that may also be employed in which the above mentionedphosphonic acid diester of formula (Iq) is reacted with two or moremolar equivalents of a mineral acid such as HCl or sulfuric acid inwater with or without a co-solvent such as THF at temperatures rangingfrom 40 to 100° C. Still alternatively, many other conditions may beemployed to effect the above mentioned diester to acid transformationleading to (Iq). These include reacting the phosphonic acid diester offormula (Iq) with two or more molar equivalents of boron tribromide orboron trichloride in dichloromethane at −78° C. to room temperature; twoor more molar equivalents hydrobromic acid in acetic acid at 0° C. to50° C.; two or more molar equivalents trimethylsilylbromide ortrimethylsilyliodide in dichloromethane, carbon tetrachloride oracetonitrile at −78° C. to 50° C.; two or more molar equivalents lithiumiodide in pyridine or quinoline at temperatures from 60° to 250° C.

[0163] The esters of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl;,W isCO₂R⁶; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl), R⁶is alkyl of1-6 carbon atoms; E is S or O) can be transformed into their primarycarboxylic acid amide analogs of formula (Iq: B, D is H, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkylof 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbonatoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹,SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; W is CONH₂; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl) ; E is S or O)by reacting the ester starting material with ammonia gas dissolved in alower alcohol solvent such as methanol or ethanol at temperaturesranging from 0° C. to 100° C.

[0164] Alternatively, the carboxylic acids of formula (Iq: B, D is H,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is CO₂H; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl) ; E is S or O)can be transformed into their carboxylic acid amide analogs of formula(Iq: B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl,nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W isCONH₂, CONHOH, CONH(CH,)₂CN; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl); E is S or O).This transformation can be accomplished using standard methods to effectcarboxylic acid to carboxylic acid amide transformations. These methodsinclude converting the acid to an activated acid and reacting with oneor more molar equivalents of the desired amine. Amines in this categoryinclude ammonia in the form of ammonium hydroxide, hydroxyl amine and2-aminopropionitrile. Methods to activate the carboxylic acid includereacting said acid with one or more molar equivalents of oxalyl chlorideor thionyl chloride to afford the carboxylic acid chloride in a suitablesolvent such as dichloromethane, chloroform or diethyl ether. Thisreaction is often catalyzed by adding small amounts (0.01 to 0.1 molarequivalents) of dimethylformamide. Other methods to activate thecarboxylic acid include reacting said acid with one or more molarequivalents dicyclohexylcarbodiimide with or without one or more molarequivalents of hydroxybenzotriazole in a suitable solvent such asdichloromethane or dimethylformamide at temperatures ranging from 0° C.to 60° C.

[0165] The phenols of formula (Ip: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Br, OR¹, SR¹, NR¹R², whereR¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O)can be alkylated with one or more molar equivalents of ahaloacetonitrile of formula (X²CH₂CN where X² is Cl, Br or I) and withone or more molar equivalents of an alkali metal carbonate such aspotassium carbonate in a polar aprotic solvent such as DMF to afford thenitriles of formula (Iq: B, D is H, halogen, CN, alkyl of 1-6 carbonatoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; W is CN;R⁵is H; E is S or O).

[0166] Alternatively, the carboxylic acid amide analogs of formula (Iq:B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;Y is H, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is CONH₂; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl); E is S or O)can be converted to their nitrile analogs of formula (Iq: B, D is H,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is CONH₂; R⁵ is H, alkyl of 1-6 carbon atoms,aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl); E is S or O) byusing reagents that dehydrate the primary carboxamide function to thenitrile function. One set of conditions to effect this transformationinclude reacting the said primary carboxylic acid amide with one or moremolar equivalents of trifluoroacetic anhydride and two or more molarequivalents of pyridine in a suitable solvent such as dioxane attemperatures ranging from 60° C. to 120° C.

[0167] The nitriles analogs of formula (Iq: B, D is H, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkylof 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbonatoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹,SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; W is CN; R⁵ is H, alkyl of 1-6 carbon atoms, aralkyl, aryl,CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl); E is S or O)can be converted to the tetrazoles of formula (Iq: B, D is H, halogen,CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; W is 5-tetrazole; R⁵ is H, alkyl of 1-6 carbonatoms, aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂(3-1H-indolyl),CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂(3-pyridyl); E is S or O) byreacting the nitrile function with one or more molar equivalents oftrimethylaluminum and one or more molar equivalents of trimethylsilylazide in a suitable solvent such as benzene or toluene at temperaturesranging from 60° C. to 120° C. Alternatively, the nitrile fuction can bereacted with one or more molar equivalents of ammonium azide in asuitable solvent such as dimethylformamide at temperatures ranging from60° C. to 160° C.

[0168] Further derivatives of the compounds of formula (I) in Scheme 10can be prepared by the following methods. The phenols of formula (Ir: B,D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl;Y is H, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; E is S or O) can be reacted with one or moremolar equivalents of lithium (bis)trimethylsilylamide at temperautresranging from −78° C. to room temperature and the lithium salt can befurther reacted with one or more molar equivalents of5-bromothiazolidine-2, 4-dione (prepared according to the method ofZask, et al., J. Med Chem, 1990, 33, 1418-1423) using a suitable solventsuch as THF under an inert atmosphere at temperautres ranging from −78°C. to room temperature to provide the compounds of formula (Is: R⁴ is(R, S)-5-thiazolidine-2,4-dione; B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO).

[0169] Alternatively, the phenols of formula (Ir: B, D is H, halogen,CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; E is S or O) can be reacted with one or moremolar equivalents of tetrazole and di-tert-butylN,N-diethylphosporamidate in THF at room temperature followed byaddition of one or more molar equivalents of meta-chlorobenzoic acid at−40° C. according to the procedure of J. W. Perich and R. B. Johns,Synthesis, 1988, 142-144) to afford the phosphate diesters of formula(Is: R⁴ is P(O)(OtBu)₂; B, D is H, halogen, CN, alkyl of 1-6 carbonatoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms,CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO). These phosphate diesters are then treated with one or more molarequivalents hydrochloric acid in a suitable solvent such as dioxane toprovide the phosphonic acids of formula (Is: R⁴ is P(O)(OH)₂; B, D is H,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; E is S or O).

[0170] The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be transformed to the carboxylic acids of formula (Is: R⁴ isC(CH₃)₂CO₂H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) by treatment of the phenols with two or more molar equivalents ofsolid sodium hydroxide followed by one or more molar equivalents of1,1,1-trichloro-2-methyl-2-propanol tetrahydrate in the presence of alarge excess of acetone which also serves as solvent.

[0171] The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be transformed to the carboxylic acids of formula (Is: R⁴ isCH₂CH₂CO₂H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) by treatment with one or more molar equivalents of β-propiolactoneand treatment with one or more molar equivalents of potassiumtert-butoxide in a suitable solvent such as THF.

[0172] The phenols of formula (Ir: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be reacted with a 3-hydroxy carboxylic acid ester of formulaCH(OH)(R⁷)CH₂CO₂R⁶ (R⁷ is H or alkyl of 1-6 carbon atoms; R⁶ is alkyl of1-6 carbon atoms) to afford the esters of formula (Is: B, D is H,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylamino-ethylsulfanyl; Y isH, Cl, Br, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; E is S or O) under the conditions of theMitsunobu Reactions (for a review see Oyo Mitsunobu Synthesis 1981,1-27). The other co-reagents necessary to effect the Mitsunobu Reactioninclude one or more molar equivalents of a alkyl of 1-6 carbon atomsazodicarboxylate diester such as diethyl azodicarboxylate or diisopropylazodicarboxylate and one or more molar equivalents of triarylphosphinesuch as triphenylphosphine in a suitable solvent such as diethyl ether,THF, benzene or toluene at temperatures ranging from −20° C. to 120° C.at temperatures ranging from −20° C. to 120° C.

[0173] The 3-hydroxy carboxylic acid ester of formula CH(OH)(R⁷)CH₂CO₂R⁶(R⁷ is H or alkyl of 1-6 carbon atoms; R⁶ is alkyl of 1-6 carbon atoms)are commercially available or can be prepared from commerciallyavailable carboxylic acid precursors under standard esterificationconditions.

[0174] The esters of formula (Is: B, D is H, halogen, CN, alkyl of 1-6carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) can be transformed to the acids of formula (Is: R⁴ is(R)-CH(R⁷)CH₂CO₂H; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms,aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN,lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro,alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylamino-ethylsulfanyl; Y is H, Cl, Br, OR¹, SR¹, NR¹R²,where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S orO) by several standard conditions which include reacting the ester offormula (Is) with two or more molar equivalents of a mineral acid suchas HCl or sulfuric acid in one or more solvents or a combination of twoor more solvents such as water, THF or dioxane at temperatures rangingfrom 40 to 120° C. Still alternatively, many other conditions may beemployed to effect the above mentioned ester to acid transformationleading to (Is). These include reacting the esters of formula (Is) withtwo or more molar equivalents of boron tribromide or boron trichloridein dichloromethane at −78° C. to room temperature; two or more molarequivalents hydrobromic acid in acetic acid at 0° C. to 50° C.; two ormore molar equivalents trimethylsilylbromide or trimethylsilyliodide indichloromethane, carbon tetrachloride or acetonitrile at −78° C. to 50°C.; two or more molar equivalents lithium iodide in pyridine orquinoline at temperatures from 60° to 250° C.

[0175] The nitrophenols of formula (Ir: B is NO₂; D is H or Br; X is H,halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H,OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O) can be alkylated with one or more molarequivalents of an alkyl or aralkyl halide of formula (XR⁴ where X is Cl,Br or I and R⁴ is alkyl of 1-6 carbon atoms, aralkyl ) and with one ormore molar equivalents of an alkali metal carbonate such as potassiumcarbonate in a polar aprotic solvent such as DMF to afford the alkylatedproduct of formula (Is: B is NO₂; D is H or Br; X is H, halogen, alkylof 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbonatoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR¹, SR¹,NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; Eis S or O; R⁴ is alkyl of 1-6 carbon atoms, aralkyl).

[0176] The nitro compounds of formula (Is: B is NO₂; D is H or Br; X isH, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxyof 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H,OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O; R⁴ is alkyl of 1-6 carbon atoms, aralkyl) can bereduced to the amino compounds of formula (Is: B is NH₂; D is H or Br; Xis H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbonatoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;Y is H, OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms,aryl or aralkyl; E is S or O; R⁴ is alkyl of 1-6 carbon atoms, aralkyl)most readily using tin dichloride in ethylacetate at 40 to 100° C. orwith hydrazine and Montmorillinite clay in ethanol at 40 to 100° C.

[0177] The amino compounds of formula (Is: B is NH₂; D is H or Br; X isH, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxyof 1-6 carbon atoms, aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms,arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H,OR¹, SR¹, NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; E is S or O; R⁴ is alkyl of 1-6 carbon atoms, aralkyl) can bealkylated with one or more molar equivalents of an alkyl haloacetate offormula (X²CHR^(6a)CO₂R⁶ where X² is Cl, Br or I and R⁶ is alkyl of 1-6carbon atoms, R^(6a) is H) and with one or more molar equivalents of analkali metal carbonate such as potassium carbonate in a polar aproticsolvent such as DMF to afford the alkylated product of formula (Is: B isNCHR^(6a)CO₂R⁶; R⁶ is alkyl of 1-6 carbon atoms; R^(6a) is H or alkyl of1-6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1-6 carbonatoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy,nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl; Y is H, OR¹, SR¹, NR¹R², where R¹, R²is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; E is S or O; R⁴ isalkyl of 1-6 carbon atoms, aralkyl). These esters can be transformedinto their carboxylic acid analogs using standard conditions to affordthe carboxylic acids of formula (Is: B is NCHR^(6a)CO₂H; R^(6a) is H oralkyl of 1-6 carbon atoms; D is H or Br; X is H, halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl; Y is H, OR¹, SR¹,NR¹R², where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; Eis S or O; R⁴ is alkyl of 1-6 carbon atoms, aralkyl). The conditions toeffect these transformations include aqueous base in which one or moremolar equivalents of alkali metal hydroxide such as sodium hydroxide isused in water with a co-solvent such as THF, dioxane or a lower alcoholsuch as methanol or mixtures of THF and a lower alcohol at temperaturesranging from 0° C. to 40° C.

[0178] Further derivatives of the compounds of formula (I) in Scheme 11can be prepared by the following methods. The compounds of formula (It:B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro;X is H, halogen, alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl,alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR′ where R¹,R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R⁵ is H, alkyl of1-6 carbon atoms, aryl or aralkyl; R⁶ is H, alkyl of 1-6 carbon atoms)can be transformed into their sulfoxide derivatives of formula (Iu: n is1; B, D is H, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl,nitro; X is H, halogen, alkyl of 1-6 carbon atoms, CN, lowerperfluoroalkyl, alkoxy of 1-6 carbon atoms, aralkoxy, nitro; Y is Cl,Br, OR¹ where R¹, R² is H, alkyl of 1-6 carbon atoms, aryl or aralkyl;R⁵ is H, alkyl of 1-6 carbon atoms, aryl or aralkyl; R⁶ is H, alkyl of1-6 carbon atoms) using one molar equivalent of an oxidizing agent suchas m-chloroperbenzoic acid in dichloromethane at temperatures rangingfrom −20° C. to 40° C. or peracetic aid in acetic acid and water attemperatures ranging from room temperature to 100° C.

[0179] The compounds of formula (It: B, D is H, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen, alkyl of 1-6carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6 carbon atoms,aralkoxy, nitro; Y is Cl, Br, OR¹ where R¹, R² is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; R′ is H, alkyl of 1-6 carbon atoms, aryl oraralkyl; R⁶ is H, alkyl of 1-6 carbon atoms) can be transformed intotheir sulfone derivatives of formula (Iu: n is 2; B, D is H, halogen,CN, alkyl of 1-6 carbon atoms, aryl, aralkyl, nitro; X is H, halogen,alkyl of 1-6 carbon atoms, CN, lower perfluoroalkyl, alkoxy of 1-6carbon atoms, aralkoxy, nitro; Y is Cl, Br, OR¹ where R¹, R² is H, alkylof 1-6 carbon atoms, aryl or aralkyl; R⁵ is H, alkyl of 1-6 carbonatoms, aryl or aralkyl; R⁶ is H, alkyl of 1-6 carbon atoms) using two ormore molar equivalents of an oxidizing agent such as m-chloroperbenzoicacid in dichloromethane at temperatures ranging from −20° C. to 60° C.or peracetic aid in acetic acid and water at temperatures ranging fromroom temperature to 100° C.

[0180] The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

[0181] The ability of compounds of this invention to treat or inhibitdisorders related to insulin resistance or hyperglycemia was establishedwith representative compounds of this invention in the following twostandard pharmacological test procedures which measure the inhibition ofPTPase.

[0182] Inhibition of Tri-Phosphorylated Insulin ReceptorDodecaphosphopeptide Dephosphorylation by Rat Hepatic Protein-TyrosinePhosphatases (PTPases)

[0183] This standard pharmacological test procedure assess theinhibition of rat hepatic microsomal PTPase activity using, assubstrate, the phosphotyrosyl dodecapeptide corresponding to the1142-1153 insulin receptor kinase domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues. The procedure used and results obtainedare briefly outlined below.

[0184] Preparation of Microsomal Fraction: Rats (Male Sprague-Dawleyrats (Charles River, Kingston, N.Y.) weighing 100-150 g, maintained onstandard rodent chow (Purina)) are sacrificed by asphyxiation with CO2and bilateral thoracotomy. The liver is removed and washed in cold 0.85%(w/v) saline and weighed. The tissue is homogenized on ice in 10 volumesof Buffer A and the microsomes are isolated essentially as described byMeyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn C R.Vanadate normalizes hyperglycemia in two mouse models ofnon-insulin-dependent diabetes mellitus. J Clin Invest 1991;87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD, editors. Molecular biology of the cell. New York: Garland Publishing,Inc., 1989 with minor modifications. The liver homogenate is filteredthrough silk to remove any remaining tissue debris and then iscentrifuged at 10,000×g for 20 minutes at 40C. The supernatant isdecanted and centrifuged at 100,000×g for 60 minutes at 40C. The pellet,microsomes and small vesicles, is resuspended and lightly homogenizedin: 20 mM TRIS-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mM sucrose, 2mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK, 0.5 mMbenzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H5Bantipain, 5 ug/ml chymostatin, 10 ug/mil aprotinin (Buffer A), to afinal concentration of approximately 850 ug protein/ml. Proteinconcentration is determined by the Pierce Coomassie Plus Protein Assayusing crystalline bovine serum albumin as a standard (Pierce ChemicalCo., Rockford, Ill.).

[0185] Measurement of PTPase activity: The malachite green-ammoniummolybdate method, as described by Lanzetta P A, Alvarez L J, Reinach PS, Candia O A was used. An improved assay for nanomolar amounts ofinorganic phosphate. Anal. Biochem. 1979;100:95-97, and adapted for theplatereader, is used for the nanomolar detection of liberated phosphateby rat hepatic microsomal PTPases. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). The peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150 and 1151 tyrosine residues. Themicrosomal fraction (83.25 ul) is preincubated for 10 min at 37 deg.Cwith or without test compound (6.25 ul) and 305.5 ul of the 81.83 mMHEPES reaction buffer, pH 7.4. Peptide substrate, 10.5 ul at a finalconcentration of 50 uM, is equilibrated to 37 deg.C in a LABLINEMulti-Blok heater equipped with a titerplate adapter. The preincubatedmicrosomal preparation (39.5 ul) with or without drug is added toinitiate the dephosphorylation reaction, which proceeds at 37 deg.C for30 min. The reaction is terminated by the addition of 200 ul of themalachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).The stopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 ulMG/AM/Tw to substrate and followed by 39.5 ul of the preincubatedmembrane with or without drug. The color is allowed to develop at roomtemperature for 30 min and the sample absorbances are determined at 650nm using a platereader (Molecular Devices). Samples and blanks areprepared in quadruplicates. Screening activity of 50 uM (final) drug isaccessed for inhibition of microsomal PTPases.

[0186] Calculations: PTPase activities, based on a potassium phosphatestandard curve, are expressed as nmoles of phosphate released/min/mgprotein. Test compound PTPase inhibition is calculated as percent ofcontrol. A four parameter non-linear logistic regression of PTPaseactivities using SAS release 6.08, PROC NLIN, is used for determiningIC50 values of test compounds. All compounds were administered at aconcentration of 50 μM. The following results were obtained usingrepresentative compounds of this invention. % Change from ExampleControl  9 −49.80 19 −30.40 20 2.13 21 −63.12 22 −28.57 23 −26.11 24−65.31 29 −83.54 30 −60.32 31 −63.42 32 −89.41 33 −61.92 34 −63.01 35−58.85 36 −67.00 37 −49.83 38 −57.74 40 −83.88 41 −39.60 42 −63.41 43−78.84 44 −68.50 45 −94.50 46 −91.00 47 −68.48 48 −44.69 49 −89.36 50−81.27 52 −87.66 53 −81.83 Phenylarsine oxide −57.06 (referencestandard)

[0187] Inhibition of Tri-Phosphorylated Insulin ReceptorDodecaphosphopeptide Dephosphorylation by hPTP1B

[0188] This standard pharmacological test procedure assess theinhibition of recombinant rat protein phosphatase, PTP1B, activityusing, as substrate, the phosphotyrosyl dodecapeptide corresponding tothe 1142-1153 insulin receptor kinase domain, phosphorylated on the1146, 1150 and 1151 tyrosine residues. The procedure used and resultsobtained are briefly described below.

[0189] Human recombinant PTP1B was prepared as described by Goldstein(see Goldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzymepreparation used was in microtubes containing 500-700 μg/ml protein in33 mM Tris-HCl, 2 MM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

[0190] Measurement of PTPase activity. The malachite green-ammoniummolybdate method, as described (Lanzetta et al. Anal. Biochem. 100, 95,1979) and adapted for a platereader, is used for the nanomolar detectionof liberated phosphate by recombinant PTP1B. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). the peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150, and 1151 tyrosine residues. Therecombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 mMTris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain anapproximate activity of 1000-2000 nmoles/min/mg protein. The dilutedenzyme (83.25 mL) is preincubated for 10 min at 37° C. with or withouttest compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reactionbuffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50mM, and is equilibrated to 37° C. in a LABLINE Multi-Blok heaterequipped with a titerplate adapter. The preincubated recombinant enzymepreparation (39.5 ml) with or without drug is added to initiate thedephosphorylation reaction, which proceeds at 37° C. for 30 min. Thereaction is terminated by the addition of 200 mL of the malachitegreen-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). Thestopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mLMG/AM/Tw to substrate and followed by 39.5 ml of the preincubatedrecombinant enzyme with or without drug. The color is allowed to developat room temperature for 30 min. and the sample absorbances aredetermined at 650 nm using a platereader (Molecular Devices). Sample andblanks are prepared in quadruplicates.

[0191] Calculations: PTPase activities, based on a potassium phosphatestandard curve, are expressed as nmoles of phosphate released/min/mgprotein. Inhibition of recombinant PTP1B by test compounds is calculatedas percent of phosphatase control. A four parameter non-linear logisticregression of PTPase activities using SAS release 6.08, PROC NLIN, isused for determining IC₅₀ values of test compounds. The followingresults were obtained. Example IC50 (μM)  9 0.539 19 0.697 21 0.381 230.743 29 0.115 30 0.869 31 0.049 32 0.060 33 0.029 34 0.100 35 0.273 361.34 37 0.352 38 0.299 39 1.74 40 0.110 41 0.729 42 0.089 43 0.171 440.237 45 0.203 46 1.19 47 0.095 48 0.083 49 0.384 50 0.457 51 2.21 520.287 53 0.204 54 0.982 55 0.059 56 0.489 57 1.90 59 2.20 60 1.51 610.164 62 0.028 63 0.138 64 0.39 65 0.36 68 0.080 70 0.33 71 1.19 72 0.4876 0.45 78 0.27 79 0.78 83 0.13 88 0.32 Phenylarsine oxide 39.7(reference standard) Sodium orthovanadate 244.8 (reference standard)Ammonium molybdate 8.7 tetrahydrate (reference standard)

[0192] The blood glucose lowering activity of representative compoundsof this invention were demonstrated in an in vivo standard procedureusing diabetic (ob/ob) mice. The procedures used and results obtainedare briefly described below.

[0193] The non-insulin dependent diabetic (NIDDM) syndrome can betypically characterizes by obesity, hyperglycemia, abnormal insulinsecretion, hyperinsulinemia and insulin resistance. The geneticallyobese-hyperglycemic ob/ob mouse exhibits many of these metabolicabnormalities and is thought to be a useful model to search forhypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14:141-148, 1978].

[0194] In each test procedure, mice [Male or female ob/ob (C57 B1/6J)and their lean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to5 months (10 to 65 g)] of a similar age were randomized according tobody weight into 4 groups of 10 mice. The mice were housed 5 per cageand are maintained on normal rodent chow with water ad libitum. Micereceived test compound daily by gavage (suspended in 0.5 ml of 0.5%methyl cellulose); dissolved in the drinking water; or admixed in thediet. The dose of compounds given ranges from 2.5 to 200 mg/kg bodyweight/day. The dose is calculated based on the fed weekly body weightand is expressed as active moiety. The positive control, ciglitazone(5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-dione, see Chang, A., Wyse,B., Peterson, T. and Diani, A. Diabetes 32: 830-838, 1983.) was given ata dose of 100 mg/kg/day, which produces a significant lowering in plasmaglucose. Control mice received vehicle only.

[0195] On the morning of Day 4, 7 or 14 two drops of blood (approximetly50 ul) were collected into sodium fluoride containing tubes either fromthe tail vein or after decapitation. For those studies in which thecompound was administered daily by gavage the blood samples werecollected 0 and 4 hours after compound administration. The plasma wasisolated by centrifugation and the concentration of glucose is measuredenzymatically on an Abbott V. P. Analyzer.

[0196] For each mouse, the percentage change in plasma glucose on Day 4,7 or 14 is calculated relative to the mean plasma glucose of the vehicletreated mice. Analysis of variance followed by Dunett's Comparison Test(one-tailed) are used to estimate the significant difference between theplasma glucose values from the control group and the individual compoundtreated groups (CMS SAS Release 5.18).

[0197] The results shown in the table below shows that the compounds ofthis invention are antihyperglycemic agents as they lower blood glucoselevels in diabetic mice. % Change Glucose from % Change Insulin fromExample Dose (mg/Kg) Vehicle Vehicle 29 100 −48.63 −89.59 29 25 −38.18−80.50 29 10 −18.6 (a) −48.11 32 25 −15.68 (a) −48.35 33 25 −21.10 (a)−39.3 35 25 −25.58 −2.98 (a) 40 100 −28.20 −90.80 42 25 −32.5 b 43 25−45.2 b 44 25 −17.2 b 48 25 −20.1 b 49 10 −35.1 b 61 10 −32.8 (c) bCiglitazone 100 −43 −39 (reference standard

[0198] a—no significant activity (p<0.05) at this dose.

[0199] b—not measured

[0200] c—measured at 0 hour

[0201] Based on the results obtained in the standard pharmacologicaltest procedures, representative compounds of this invention have beenshown to inhibit PTPase activity and lower blood glucose levels indiabetic mice, and are therefore useful in treating metabolic disordersrelated to insulin resistance or hyperglycemia, typically associatedwith obesity or glucose intolerance. More particularly, the compounds ofthis invention useful in the treatment or inhibition of type IIdiabetes, and in modulating glucose levels in disorders such as type Idiabetes. As used herein, the term modulating means maintaining glucoselevels within clinically normal ranges.

[0202] Effective administration of these compounds may be given at adaily dosage of from about 1 mg/kg to about 250 mg/kg, and may given ina single dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, via implants,parenterally (including intravenous, intraperitoneal and subcutaneousinjections), rectally, vaginally, and transdermally. For the purposes ofthis disclosure, transdermal administrations are understood to includeall administrations across the surface of the body and the inner liningsof bodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0203] Oral formulations containing the active compounds of thisinvention may comprise any conventionally used oral forms, includingtablets, capsules, buccal forms, troches, lozenges and oral liquids,suspensions or solutions. Capsules may contain mixtures of the activecompound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0204] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the malady andthe individual being treated and will be subject to the judgment of themedical practitioner involved. It is preferred that the administrationof one or more of the compounds herein begin at a low dose and beincreased until the desired effects are achieved.

[0205] The following procedures describe the preparation ofrepresentative examples of this invention.

Example 1

[0206]2,3- Dimethyl-thiophene

[0207] A mixture of 3-methyl-thiophene-carboxaldehyde (20 g, 0.159 mol),hydrazine hydrate (31 mL) and diethylene glycol (72 mL) was heated toreflux for 20 min. After cooling below 100° C., potassium hydroxide(22.9 g, 0.408 mol) was added and the reaction mixture was heated at125-130° C. for 1.5 h. The reaction mixture was cooled to roomtemperature and added to water. This aqueous mixture was extracted withether and the ether phase was washed with 5% aqueous HCl and brine.After drying (magnisium sulfate) the solvent was removed and the oil wasflash chromatograghed (pentane as eluent) to provide the title compoundas an oil (15.81 g, 89%): NMR (CDCl3); δ 6.97 (d, 1H, J=8 Hz), 6.77 (d,1H, J=8 Hz), 2.35 (s, 3H), 2.14 (s, 3H).

Example 2

[0208] 4, 5-Dimethylthiophene-2-yl-(phenyl)-methanol

[0209] n-Butyl lithium (19.6 ml, 49.1 mmol, 2.5 N in hexanes) was addeddropwise to a stirred solution of 2,3- dimethyl-thiophene (5.0 g, 44.6mmol) in THF (100 mL) at −78° C. under a dry nitrogen atmosphere. Thesolution was warmed to 0° C. for 30 min and recooled to −78° C.whereupon benzaldehyde (5.0 mL, 49.1 mmol) was added. After anadditional 45 minutes, sat. aq. ammonium chloride was added and thereaction mixture was partitioned between water and ether. The etherphase was washed with brine and concentrated. The resultant oil wastriturated with pet. ether to provide the title compound as a whitesolid (7.77 g, 80%): mp 80-81° C.: NMR (CDCl3); δ 7.45 (ddd, J=8, 1, 1Hz, 2H), 7.37 (ddd, J=8, 8, 1 Hz, 2H), 7.3 (m, 1H), 6.57 (s, 1H), 6.93(s, 1H, OH), 2.29 (s, 3H), 2.05 (s, 3H); MS (El) (M+) 218 (45%, MI):Anal. Calc. for C13H14OS: C, 71.52, H, 6.46, N, 0.00. Found: C, 71.41,H, 6.42, N, 0.09.

Example 3

[0210] 2-Benzyl-4, 5 dimethylthiophene

[0211] Trifluoroacetic acid (50 mL) was added dropwise over a 60 minuteperiod to a stirred, 0° C. suspension of 4,5-dimethylthiophene-2-yl-(phenyl)-methanol (7.7 g, 35.3 mmol), sodiumborohydride (6.67 g, 177 mmol) and ether (600 mL). After an additional1.5 hours the reaction mixture was added to 10% aqueous sodium hydroxide(600 mL) and stirred for 30 minutes. The layers were separated and theether phase was washed with 10% aqueous sodium hydroxide, brine anddried (magnesium sulfate). The ether phase was concentrated to providethe tide compound as a an oil (6.73 g, 94%): NMR (CDCl3); δ 7.33-7.19(m, 5H), 6.47 (s, 1H), 4.03 (s, 2H), 2.27 (2,3H), 2.06 (s, 2H); MS (EI)(M+) 202 (45%, MI).

Example 4

[0212] (2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone

[0213] Tin tetrachloride (4.6 mL, 71.76 mmol) was added dropwise over a10 minute period to a stirred, −78° C. solution of 2-benzyl-4, 5-dimethylthiophene (6.6 g, 32.62 mmol), anisoyl chloride (5.90 g, 34.6mmol) and dichloromethane (120 mL) under a dry nitrogen atmosphere.After 5 hours at −78° C., the reaction mixture was slowly warmed to roomtemperature over a 2 h period. The reaction mixture was added to waterand extracted with ether. The ether extract was washed with sat. aq.sodium bicarbonate and brine. The solvent was removed and the resultantsolid was triturated with ether to give the title compound as aoff-white solid (9.62 g, 88%): mp 85-86° C.: NMR (CDCl3); δ 7.80 (ddd,J=8, 8, 1 Hz, 2H), 7.24-7.10 (m, 5H), 7.92 (ddd, J=8, 8, 1 Hz, 2H), 3.93(s, 2H), 3.88 (s, 3H), 2.28 (s, 3H), 1.90 (s, 3H); MS (EI): 336 (100%,MI); Anal. Calc. for C21H20O2S: C, 74.97, H, 5.99, N, 0.00. Found: C,75.11, H, 6.02, N, 0.05.

Example 5

[0214] 4-(2, 3-Dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol

[0215] Neat boron tribromide (20 mL, 212 mmol) was added dropwise to astirrred solution of (2-benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone (9.40 g, 27.9mmol) in dichloromethane (95 mL) at −78° C. under a dry nitrogenatomosphere. The solution was allowed to warm to ambient temperature andwas stirred for 4 h. The reaction mixture was cooled to 0° C. andcarefully quenched with water and the solvent was removed. More waterwas added and the resultant solid was filtered and washed with water andtriturated with pet. ether to provide the title compound as a lightpurple solid (8.23 g, 97%): mp: 165-168° C.; NMR (DMSO-d6); δ 9.62 (s,1H), 8.43 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.43 (m, 2H), 7.32 (ddd, J=8,1, 1 Hz, IH), 7.11 (d, J=8 Hz, 2H), 6.90 (d, J=9 Hz, 2H), 2.39 (s, 3H),1.61 (s, 3H); MS (EI): 304 (100%, MI).

Example 6

[0216] Acetic Acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester

[0217] Acetic anhydride (0.68 mL, 7.20 mmol) was added to a 0° C.,stirred solution of 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(2.0 g, 6.57 mmol) in pyridine (8.6 mL). After 17 h the reaction mixturewas added to 5% aqueous HCl and the resulting solid was filtered andwashed with 5% aqueous HCl, water and triturated with pet. ether. It wasthen dried in vacuo to provide the title compound as a white solid (1.99g, 88%): mp: 147-150° C.; NMR (DMSO-d6); δ 8.49 (s, 1H), 7.94 (d, J=8Hz, 1H), 7.46 (ddd, J=8, 6, 2, 1H), 7.38 (ddd, J=8, 1, 1 Hz, 1H),7.39-7.34 (m, 2H), 7.28 (d, J=8 Hz, 2H), 6.90 (d, J=9 Hz, 2H), 2.40 (d,J=1 Hz, 3H), 2.34 (s, 3H), 1.57 (d, J=1 Hz, 3H); MS (EI): 346 (90%, MI),304 (100%); Anal. Calc. for C22H18O2S: C, 76.27, H, 5.34, N. 0.00.Found: C, 75.88, H. 5.04, N, 0.28.

Example 7

[0218] Acetic Acid 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester

[0219] A solution of bromine (0.326 mL, 6.15 mmol) in dichloromethane (9mL) was added dropwise over a 15 minute period to a solution that wasstirred in the absence of light of acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.87 g, 5.41mmol) and iron (III) chloride (50 mg, 0.31 mmol) in dichloromethane (47mL) at −78° C. under a dry nitrogen atmosphere. After 10 minutes, adilute aqueous sodium bisulfite solution was added and the reactionmixture was partitioned between water and ether. The ether phase waswashed with brine and concentrated to provide the title compound as awhite solid (2.09 g, 91%): mp: 190-191° C.; NMR (DMSO-d6); 8.20 (d, J=8Hz, 1H), 7.65 (ddd, J=8, 7, 1, 1H), 7.49 (ddd, J=8, 7, 1 Hz, 1H),7.43-7.38 (m, 1H), 7.40 (d, J=9 Hz, 2H), 7.30 (d, J=9 Hz, 2H), 2.43 (d,J=1 Hz, 3H), 2.33 (s, 3H), 1.55 (d, J=1 Hz, 3H); MS (EI): 1 bromineisotope pattern 424 (95%, MI), 426 (100%); Anal. Calc. for C22H17BrO2S:C, 62.12, H, 4.03, N, 0.00. Found: C, 62.46, H, 4.05, N, 0.09.

Example 8

[0220] 4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0221] Aqueous potassium hydroxide (6.0 mL, 6.0 mmol) was added to astirred, room temperature solution of acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (0.48g, 1.14 mmol) in THF (15 mL)/methanol (10 mL). After 1 h, the organicsolvents were removed, water was added, the reaction mixture wasacidified with 10% HCl and the resulting solid was washed with water andtriturated with pet. ether and then dried in vacuo to provide the titlecompound as a white solid (0.32 g, 73%): mp: 165-168° C.; NMR (DMSO-d6);δ 9.68 (s, 1H), 8.17 (d, J=8 Hz, 1H), 7.62 (ddd, J=8, 6, 1 Hz, 1H), 7.50(d, J=8 Hz, 1H), 7.44 (ddd, J=8, 7, 1 Hz, 1H), 7.13 (d, J=9 Hz, 2H),6.91 (d, J=9 Hz, 2H), 2.42 (d, J=1 Hz, 3H), 1.59 (d, J=1 Hz, 3H); MS(EI): 1 bromine isotope pattern 382 (95%0, MI), 384 (100%); Anal. Calc.for C20H15BrOS: C, 62.67, H, 3.95, N, 0.00. Found: C, 62.40, H, 3.91, N,0.09.

Example 9

[0222] 2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0223] A solution of bromine (0.34 mL, 5,74 mmol) in acetic acid (5 mL)was added dropwise to a room temperature, stirred solution of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.10 g,2.87 mmol), potassium acetate (2.82 g, 28.7 mol) and acetic acid (31mL). After 1.5 h, water (200 mL) and a small amount of solid sodiumsulfite were added. The suspension was filtered and the solid was washedwith water, triturated with pet. ether and dried in vacou to provide thetitle compound as a white solid (1.52 g, 88%): mp 172-174° C.: NMR(DMSO-d6); 11.95 (broad s, 1H), 10.20 (broad s, 1H), 8.19 (ddd, J=8,1,1Hz, 1H), 7.65 (ddd, J=8, 6, 1 Hz, 1H), 7.59(s, 2H), 7.51-7.49 (m, 2H),2.44 (d, J=1 Hz, 3H), 1.90 (s, 3H), 1.64 (d, J=1 Hz, 3H); MS (+FAB): 3bromine isotope pattern 538 (40%), 540 (100%), 542 (90%), 544 (50%);Anal. Calc. for C22H13Br3OSC2H402: C, 43.95, H, 2.85, N, 0.00. Found: C,44.13, H, 2.66, N, 0.12.

Example 10

[0224] Methanesulfonic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester

[0225] To a cold (ice bath) solution of4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol (3.00 g, 9.86 mmol)and pyridine (4.0 mL, 49.3 mmol, 5 eq) in methylene chloride (24 mL) wasadded methylsulfonylchloride (1.14 mL, 14.8 mmol, 1.5 eq) dropwise. Thebath was removed and after stirring at ambient temperature for about 38hours the reaction mixture was combined with water (150 mL), acidifiedwith 10% hydrochloric acid and extracted with ether. The extracts werecombined and washed with brine. Silica gel was added and the solventswere removed. The adosrbate was flash chromatographed (45/55 petroleumether/ethyl acetate) to give the title compound as a white solid (30.2g, 80%): NMR (CDCl3); δ 8.30 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.50-7.40(m, 5H), 7.38-7.28 (m, 1H), 3.26 (s, 3H), 2.50 (s, 3H), 1.61 (s, 3H).

Example 11

[0226] Methanesulfonic acid4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester

[0227] To a solution of methanesulfonic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (3.00 g, 7.84mmol), in tetrahydrofuran (31.5 mL), 80% aqueous acetic acid (16 mL) andconcentrated sulfuric acid (0.87 mL) was added iodine (1.59 g, 6.27mmol, 0.8 eq) and iodic acid (0.414 g, 2.35 mmol, 0.9 eq) at roomtemperature. The mixture was stirred at room temperature for 12 days.The reaction mixture was poured into a dilute aqueous solution of sodiumbisulfite (200 mL) and the organics were extracted with ether (2×200mL). The extracts were combined and silica gel was added. The solventswere removed and the adsorbate was flash chromatographed (90/10petroleum ether/ethyl acetate) without achieving purification. Therecovered material was purified by high pressure liquid chromatographywhich gave recovered starting material (30.5%) and gave the titlecompound as a white solid (0.835 g, 30%): mp 212-213° C.; NMR (DMSO-d6);δ 8.09 (d, J=8 Hz, 1H), 7.64-7.58 (m, 1H), 7.54-7.42 (m, 5H), 7.43 (d,J=8 Hz, 1H), 3.47 (s, 3H, SO3CH3), 2.42 (s, 3H), 1.50 (s, 3H); MS(EI):[M+] 508 (100%); Anal. calc. for C21H17IO3S2, C, 49.61, H, 3.37, N,0.00. Found: C, 49.44, H, 3.52, N, 0.03.

Example 12

[0228]4-(2,3-Dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0229] To a stirred suspension of methanesulfonic acid4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (0.620g, 1.22 mmol), and copper I oxide (0.192 g, 1.34 mmol) in anhydrousN,N-dimethylformamide (10 mL) was added thiophenol (0.270 mL, 2.68 mmol)and finely ground sodium hydroxide (0.107 g, 2.68 mmol) under a dryargon atmosphere. The vessel was sealed and heated at 155° C. for 9.5hours. After stirring at ambient temperature for about 8 hours thereaction mixture was poured into water, acidified with hydrochloric acidand the organics were extracted into ether. The extracts were combined,filtered, washed with water and concentrated. The yellow solid residuewas dissolved in dioxane (8 mL) and a 2.5 N soduim hydroxide solution(4.5 mL) was added. The vial was sealed and heated at 102° C. When thereaction was done (as indicated by thin layer chromatography) themixture was cooled to room temperature, diluted with water, andacidified with hydrochloric acid. The organics were extracted withether, combined with silica gel and the solvents were removed. Theadsorbate was flash chromatographed (gradient 90/10-85/15 petroleumether/ethyl acetate) and the solvents were chased with benzene andpetroleum ether to give the tide compound as a white solid (0.426 g,85%): NMR (DMSO-d6); δ 9.70 (s, 1H, OH), 8.40 (d, J=8 Hz, 1H), 7.56-7.51(m, 2H), 7.44-7.40 (m, 1H), 7.25-7.12 (m, 5H), 7.02 (d, J=7 Hz, 2H),6.93 (d, J=9 Hz, 2H), 3.67 (s, 3H), 1.62 (s, 3H); MS(EI): [M+] 412(100%); Anal. calc. for C26H20OS2: C, 75.69, H, 4.89, N, 0.00. Found C,74.98, H, 4.86, N, 0.13.

Example 13

[0230]2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0231] To a suspension of4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.414 g, 1.00 mmol), and potassium acetate (0.982 g, 10.0 mmol) inglacial acetic acid (24 mL) was added a solution of bromine (0.114 mL,2.21 mmol) in glacial acetic acid (2.50 mL) dropwise over a period of 10minutes at room temperature. Complete dessolution occured followed bythe appearance of a precipitate. After stirring for 2 hours the reactionwas quenched with dilute aqueous sodium bisulfite, added to water (100mL), acidified with 10% hydrochloric acid and extracted with ether. Theextracts were washed with water, the layers separated and after standingovernight combined with silica gel and the solvents were removed. Theadsorbate was flash chromatographed (90/10 petroleum ether/ethylacetate) to give the title compound as an off-white solid (0.391 g,58%): NMR (DMSO-d6); δ 10.25 (s, 1H, OH), 8.42 (d, J=8 Hz, 1H), 7.65 (s,2H), 7.60-7.47 (m, 3H), 7.247.19 (m, 3H), 7.15-7.00 (m, 2H), 2.39 (s,3H), 1.62 (s, 3H).

Example 14

[0232] Acetic acid4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenylester

[0233] To a cold (ice bath) solution of acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (4.00g, 9.4 mmol) in anhydrous methylene chloride (41 mL) was added sulfurylchloride (0.76 mL, 10.3 mmol) dropwise over a period of 10 minutes.After stirring 1 hour in the ice bath the reaction was quenched withwater (100 mL) and diluted with diethyl ether. After filtering, thelayers were separated. Silica gel was added to the organic layer and thesolvents were removed. The adsorbate was flash chromatographed (gradient90/10-80/20 petroleum ether/ethyl acetate) to give the title compound asa white solid (2.57 g, 59%): NMR (DMSO-d6); δ 8.23 (d, J=8 Hz, 1H), 7.71(dd, J=8,1 Hz, 1H), 7.55-7.43 (m, 4H), 7.33-7.30 (m, 2H), 5.09 (s, 2H),2.34 (s, 3H), 1.66 (s, 3H).

Example 15

[0234]4-(9-Bromo-3-methyl-2-morpholin-4-yl)methyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0235] To a solution of acetic acid4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenylester (1.20 g, 2.61 mmol) in anhydrous N,N-dimethylformamide (12 mL) wasadded potassium carbonate (1.08 g, 7.83 mmol, 3 eq) and morpholine(0.683 mL, 7.83 mmol, 3 eq) at room temperature under a dry nitrogenatmosphere. After stirring 1.75 hours another equivalent of morpholine(0.227 mL) was added and after an addeitional 0.5 hours another 2equivalents of morpholine (0.50 mL) were added. After stirring 1 hourlonger the reaction mixture was diluted with water (125 mL) and theorganics were extracted with diethyl ether (400 mL). The layers wereseparated and silica gel was added to the organic phase. The solventswere removed and the adsorbate was flash chromatographed (gradient75/25-70/30 petroleum ether/ethyl acetate) to the title compound as anwhite solid (1.00 g, 82%): mp 250-251° C.; NMR (DMSO-d6); δ 9.69 (s,1H), 8.18 (d, J=8 Hz, 1H), 7.63 (ddd, J=8,7,1 Hz, 1H), 7.51-7.42 (m,2H), 7.13 (d, J=8 Hz, 2H), 6.91 (d, J=8 Hz, 2H), 3.71 (s, 2H), 3.60 (t,J=5 Hz, 4H), 2.50-2.48 (m, 4H), 1.65 (s, 3H); MS (EI): [M+], 1 bromineisotope pattern, 467 (10%), 469 (10%); Anal. Calc for C24H22BrNO2S: C,61.53, H, 4.73, N, 2.99. Found: C, 61.53, H, 4.88, N, 3.01.

Example 16

[0236]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate

[0237] To a suspension of4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate(1.27 g, 2.76 mmol) and potassium carbonate (1.146 g, 8.29 mmol) inanhydrous N,N-dimethylformamide (15 mL) was added dimethylamine (0.86mL, 8.29 mmol) at room temperature under a dry nitrogen atmosphere.After stirring 3 hours additional dimethylamine (0.50 mL, 4.83 mmol) wasadded and the reaction mixture was stirred at room temperature for 3hours before storing in the cold (−14° C.) overnight. After stirring anadditional 5 hours at room temperature the reaction mixture was dilutedwith water (100 mL). The organics were extracted with ether. Theextracts were combined ,silica gel was added and the solvent was removedThe adsorbate was flash chromatographed (gradient 85/15-80/20 petroleumether/ethyl acetate) to give the title compound as a yellow solid (0.332g, 26%): NMR (CHCl3); δ 8.29 (d, J=8 Hz, 1H), 7.54-7.51 (m, 2H),7.36-7.30 (m, 1H), 7.20 (d, J=8 Hz, 2H), 6.96 (m, 2H), 3.90-3.65 (broads, 2H), 2.80-2.45 (broad s, 4H), 1.69 (s, 3H), 1.26-1.00 (broad s, 6H);MS (EI): M+M/Z 453 one bromine present, 301 (58%), 302 (16%), 303 (7%),382 (100%), 383 (54%), 384 (14%), 453 (30%), 455 (30%); MS [(+)ESI]:[M+H]=496(65%), 1 bromine isotope pattern; High Resolution MS: Calc.Sample Mass: 496.09459 for Formula C25H31N3O3Cl [M+H], Measured Mass:496.09407, Mass deviation: 0.52 mmu; Anal. Calc. for C24H24BrNOS: C,63.43, H, 5.32, N, 3.08. Found: C, 62.33, H, 5.11, N, 2.75.

Example 17

[0238]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0239] To a solution of4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate(0.676 g, 1.36 mmol), in tetrahydrofuran (18 mL) and methanol (12 mL)was added an aqueous solution of potassium hydroxide (1 N, 1.63 mL)dropwise at room temperature. After stirring 1 hour the solvents wereremoved. The residue was combined with water (50 mL) and acidified with10% hydrochloric acid. The organic impurities were extracted with etherleaving a white solid at the biphase interface. The sticky solid wasfiltered, triturated with acetic acid and concentrated. This salt of thetitle compound was dissolved in tetrahydrofuran and methanol andcombined with saturated aqueous sodium bicarbonate. After stirring 20minutes the mixture was diluted with water and stirred 10 minuteslonger. The organics were extracted with ether. The ether layer waswashed with brine and concentrated to give the title compound as ayellow solid (0.490 g, 79%): NMR (DMSO-d6); δ 9.69 (s, 1H, OH), 8.18 (d,J=8 Hz, 1H), 7.63-7.59 (m, 1H), 7.51-7.43 (m, 2H), 7.14 (d, J=8 Hz, 2H),6.91 (d, J=8 Hz, 2H), 3.73 (s, 2H), 2.58-2.50 (m, 4H), 1.63 (s, 3H),1.01 (t, J=7 Hz, 6H).

Example 18

[0240]2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0241] To a solution of4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.462 g, 1.07 mmol), in 9/1 glacial acetic acid/water (10 mL) was addeda solution of bromine (0.115 mL, 2.24 mmol, 2.2 eq) in 9/1 aceticacid/water (4 mL). After stirring 1.5 hours the reaction mixture wasquenched with dilute aqueous sodium bisulfite, diluted further withwater and the organics were extracted with ether. An insoluble solid wasdecanted into a flask and stirred overnight in ether. The ether wasremoved and the solid (0.162 g, 0.265 mmol) was dissolved intetrahydrofuran (100 mL) and a 1 N aqueous solution of sodium hydroxide(0.265 mL, 0.265 mmol) was added dropwise. After stirring 20 minutes thesolvent was removed and the residue was stirred in water (100 mL). Thewater was removed by decantation and the residue was stirred inpetroleum ether overnight. The solvent was removed. The residue wasdissolved in tetrahydrofuran/ether and silica gel was added. Thesolvents were removed and the adsorbate was flash chromatographed (75/25petroleum ether/ethyl acetate) to give the desired compound as a whitesolid (0.113 g, 17%): (DMSO-d6); δ 10.3-10.1 (broad s, 1H, OH), 8.20 (d,J=8 Hz, 1H), 7.66-7.63 (m, 1H), 7.60 (s, 2H), 7.50-7.48 (m, 2H), 3.76(s, 2H), 3.28-2.60 (m, 4H), 1.02 (t, J=7 Hz, 6H); MS +FAB: M+ @ M/Z609/611/613/615 3 bromine pattern 536 (22%), 538 (68%), 540 (80%), 541(52%), 611 (22%), 613 (22%); Anal. Calc. for C24H22Br3NOS: C, 47.08, H,3.62, N, 2.29. Found: C, 47.21, H, 3.69, N, 2.21.

Example 19

[0242]2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0243] To a solution of4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.854 g, 1.82 mmol) in 9/1 acetic acid/water (17 mL) was added asolution of bromine (0.207 mL, 4.01 mmol) in 9/1 acetic acid/water (1mL). After stirring 3 hours the reaction was diluted with water (200 mL)and the organics were extracted several times with diethyl ether. Theextracts were combined, concentrated and chased with benzene to give aquantitative yield of the title compound as a yellow solid (1.18 g): mp237-240° C.; NMR (pyridine-d5); δ 8.43 (dd, J=8,1 Hz, 1H), 7.81 (s, 2H),7.71 (d, J=8 Hz, 1H), 7.62 (m, 1H), 7.50 (m, 1H), 6.20 -5.30 (broad s,1H), 3.78 (t, J=5 Hz, 4H), 3.70 (s, 2H), 2.55 (t, J=4 Hz, 4H), 1.78 (s,3H); MS (EI): [M+], 3 Bromine isotope pattern, 622 (8%), 624 (18%), 626(19%), 628 (8%); Anal. Calc. for C24H20Br3NO2S: C, 46.03, H, 3.22, N,2.24. Found: C, 45.07, H, 3.31, N, 2.05.

Example 20

[0244]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol

[0245] Ethanol (40 mL) was added to a mixture of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.98 g,5.17 mmol) and iron nitrate heptahydrate (2.09 g, 5.17 mmol) and theresultant dark blue solution was heated in a 45 ° C. oil bath for 14 h.The reaction mixture was added to dilute HCl and extracted with ether.Silica gel was added to the ether phase and the solvent was removed. Theadsorbate was flashed (95:5 petroleum ether: ethyl acetate) to providethe title compound as an orange solid (1.63 g, 74%): mp 183-185° C.: NMR(DMSO-d6); δ 11.31 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.85 (d, J=2 Hz, 1 H),7.66 (ddd, J=8, 6, 1 Hz, 1H), 7.54 (dd, J=8, 2 Hz, 1H), 7.48 (dd, J=7, 1Hz, 1H), 7.29 (d, J=8 Hz, 1H), 6.91 (d, J=9 Hz, 2H), 2.44 (d, J=1 Hz,3H), 1.61 (d, J=1 Hz, 3H); MS (EI): 1 bromine isotope pattern 427 (95%,MI), 429 (100%); Anal. Calc. for C20H14BrNO3S: C, 56.09, H, 3.29, N,3.27. Found: C, 55.55, H, 3.15, N, 3.23.

Example 21

[0246]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol

[0247] A solution of bromine (0.040 mL, 0.756 mmol) in acetic acid (0.5nL) was added dropwise to a stirred suspension of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol(0.20 g, 0.467 mmol), potassium acetate (0.228 g, 2.335 mmol) in aceticacid (4 mL). After 10 min, water was added and the reaction mixture wasextracted with ether. Silica gel was added to the ether phase and thesolvent was removed. The adsorbate was flashed (gradient: 95:5 to 85:15)to provide the tide compound as a yellow solid (0.141 g, 60%): mp129-130° C.: NMR (DMSO-d6); δ 11.30 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.03(s, 1H), 7.96 (s, 1H), 7.67 (quintuplet, J=4 Hz, 1H), 7.51 (d, J=4 Hz,2H), 2.45 (s, 3H), 1.65 (s, 3H); MS (EI): 2 bromine isotope pattern 505(40%), 507 (100%), 509 (50%); Anal. Calc. for C20H13Br2NO3S: C, 47.36,H, 2.58, N, 2.76. Found: C, 47.18, H, 2.55, N, 2.63.

Example 22

[0248] 2-Amino-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0249] Using a procedure similar to Tet. Lett. 1990, 1181-1182,Montmorillinite K10 clay (425 mg) was added to a solution of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol(0.608 g, 1.42 mmol), anhydrous hydrazine (0.276 μL, 8.95 mmol) andethanol (4.2 mL) and the suspension was heated at 85° C. for 30 min. Thereaction mixture was cooled to room temperature, added to water andextracted with ether. The ether was dried and concentrated to providethe title compound as a white solid (0.576 g, 100%): mp 173-175° C.: NMR(DMSO-d6); δ 9.26 (s, 1H), 8.14 (dd, J=8, 1 Hz, 1H), 7.63-7.58 (m, 2 H),7.42 (ddd, J=8, 6, 1 Hz, 1H), 6.78 (d, J=8 Hz, 1H), 6.54 (d, J=2 Hz,1H), 6.35 (dd, J=8, 2 Hz, 1H), 4.67 (broad s, 2H), 2.42 (s, 3H), 1.69(s, 3H); MS (+FAB): 1 bromine isotope pattern 398 (30%, M+H), 400 (30%,M+H); Anal. Calc. for C20H16BrNOS: C, 60.31, H, 4.05, N, 3.52; Found: C,61.36, H, 4.08, N, 3.25.

Example 23

[0250]2-Amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0251] Using a procedure similar to Tet. Lett. 1990, 1181-1182,Montmorillinite K10 clay (1.4 g) was added to a solution of2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol(1.2 g, 2.37 mmol), anhydrous hydrazine (1 mL) and ethanol (7.2 mL) andthe suspension was heated at 85° C. for 1 h. The reaction mixture wascooled to room temperature and concentrated. The residue was twice flashchromatographed (first time, eluent: ether, second time, eluent: 4:1petrolerum ether ethyl acetate) to provide the title compound as a whitesolid (0.741 g, 66%): NMR (DMSO-d6); δ 8.16 (ddd, J=8, 1, 1 Hz, 1H),7.65-7.60 (m, 2 H), 7.47 (ddd, J=8, 6, 1 Hz, 1H), 6.65 (d, J=2 Hz, 1H),6.57 (d, J=2 Hz, 1H), 2.43 (d, J=1 Hz, 3H), 1.73 (d, J=1 Hz, 3H); MS(EI): 2 bromine isotope pattern 475 (50%, M+H), 477 (100%, M+H), 479(50%, M+H); Anal. Calc. for C20H15Br2NOS: C, 50.34, H, 3.17, N, 2.94.Found: C, 51.35, H, 3.35, N, 2.72.

Example 24

[0252][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-aceticacid

[0253] Methyl bromoacetate (0.150 mL, 1.58 mmol) was added to a stirredsuspension of potassium carbonate (0.223 g, 1.61 mmol),2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol(0.400 g, 0.789 mmol) in DMF (2.8 mL). After 15 h, the reaction mixturewas added to water and extracted with ethyl acetate. Silica gel wasadded to the ethyl acetate and the solvent was removed. The adsorbatewas flashed (9:1 petroleum ether: ethyl actetate) to provide the titlecompound as a yellow solid (0.305 g, 67%). This solid (0.050 g, 0.086mmol) was dissolved in 1:1 THF:methanol (2 mL) and treated with aqueouspotassium hydroxide (1.0 N, 0.30 mL, 0.30 mmol). After 25 min thereaction mixture was diluted with water, acidified with 10% aqeous HCland extracted with ether. The ether phase was dried (sodium sulfate),concentrated and recrystallized from petroleum ether:ether to providethe title compound as a white solid (0.025 g, 51%): mp 228-229° C.: NMR(DMSO-d6); δ 8.23 (d, J=9 Hz, 1H), 8.14 (d, J=2 Hz, 1H), 8.04 (d, J=2Hz, 1H), 7.69 (ddd, J=8, 7, 1, 1H), 7.54 (ddd, J=8, 7, 1 Hz, 1H), 7.48(d, J=8 Hz, 1H), 4.87 (d, J=6 Hz, 1H), 4.82 (d, J=6 Hz, 1H), 2.46 (s,3H), 1.62 (s, 3H); MS (+FAB): 2 bromine isotope pattern 563 (40%), 565(100%), 567 (50%); Anal. Calc. for C22H15Br2NO5S: C, 46.75, H, 2.68, N,2.48. Found: C, 45.18, H, 2.66, N, 2.38.

Example 25

[0254] (S)-2-Hydroxy-3-phenylpropionic acid, methyl ester

[0255] A solution of commercially available(S)-2-hydroxy-3-phenylpropionic acid (5.0 g, 30.1 mmol) andp-toluenesulfonic acid hydrate (1 g) in methanol (125 mL) was refluxedwith removal of water using 3A molecular sieves for 17 h. The solutionwas concentrated and dissolved in ether. The ether solution was washedwith saturated sodium bicarbonate, brine and concentrated to provide thetitle compound as a white solid (5.32 g, 98%): NMR (CDCl3); δ 7.36-7.20(m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H), 3.78 (s, 3H), 3.14 (dd, J=5, 14Hz, 1H), 2.97 ( dd, J=7, 14 Hz), 2.69 (d, J=6 Hz, 1H).

Example 26

[0256] (S)-2-[4-Nitrobenzoyl]-4-phenylbutyric acid, ethyl ester

[0257] To a cold (ice bath) solution of commercially available(R)-2-hydroxy-4-phenyl-butyrate, ethyl ester (1.86 mL, 9.60 mmole),p-nitrobenzoic acid (6.42 g, 38.4 mmole, 4 eq) and triphenylphosphine(10.07 g, 38.4 mmole, 4 eq.) in anhydrous tetrahydrofuran (110 mL) wasadded diethyl azodicarboxylate (6.05 mL, 38.4 mmole, 4 eq) dropwise overa period of 40 minutes keeping the internal temperature between 4 and 5°C. After stirring for one additional hour at 4-5° C., the ice bath wasremoved and the solution was allowed to stir at ambient temperature for5 days. The solvents were removed and the residue was redissolved in amixture of ether and ethyl acetate (600 mL). Silica gel (200 mL) wasadded and the solvents removed. The adsorbate was flash chromatographed(gradient (80/20-70/30 petroleum ether/ethyl acetate) to give the titlecompound as a yellow oil (4.03 g): NMR (CDCl3); δ 8.30 (d, J=9 Hz, 2H),8.18 (d, J=9 Hz, 2H), 7.38-7.18(m, 5H), 5.28 (t, J=2 Hz, 1H), 4.23(q,J=7 Hz, 2H), 2.85 (t, J=8 Hz, 2H), 2.40-2.33 (m, 2H), 1.29 (t, J=7H,3H); MS [(+) FAB]: [M +H] m/z=358.

Example 27

[0258] (S)-2-Hydroxy-4-phenylbutyric Acid, ethyl ester

[0259] To a suspension of potassium cyanide (0.176 g, 2.70 mmole) inabsolute ethanol (43mL) was added a solution of(S)-2-[4-nitrobenzoyl]-4-phenylbutyric acid, ethyl ester (3.86 g, 10.8mmole) in absolute ethanol (38 mL) dropwise over a period of 0.5 hours.After stirring 2.25 hours the solvent was removed and the reside wasdiluted with water and acidified with dilute hydrochloric acid. Theorganics were extracted with ether. The extracts were combined, silicagel (60 mL) was added and the solvent was removed. The adsorbate wasflash chromatographed, eluent (gradient 90/10-80/20 petroleumether/ethyl acetate) and the solvents were chased with benzene to givethe title compound as a yellow oil (1.67 g, 74%): NMR (CDCl3); δ7.38-7.16 (m, 5H), 4.30-4.10(m, 3H), 2.9-2.6 (m, 3H,), 2.2 - 1.9(m, 2H),1.15(t, 4 Hz, 3H); [a]25D +178.23 at 10.98 mg/mL CHCl3.

Example 28

[0260] (R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen4-yl)-phenoxy]3-phenyl-propionicacid methyl ester

[0261] Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwiseto a stirred, room temperature solution of2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methylester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) andbenzene (5 mL) and the solution was heated in an 80° C. oil bath for 6h. Upon cooling to room temperature, the reaction mixture was dilutedwith ether and silica gel (30 mL) was added. The reaction mixture wasconcentrated and the silica adsorbate was flash chromatographed (95:5petroleum ether:ethyl acetate) to provide the title compound as a whitesolid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ 8.21 (ddd, J=8,1,1Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24(m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz,1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz,3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704(75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30, N,0.00. Found: C, 51.52, H, 3.36, N, 0.12.

Example 29

[0262](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid

[0263] Aqueous potassium hydroxide (1 N, 2.00 mL, 2.00 mmol) was addedto a stirred solution of(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid methyl ester (0.699 g, 0.99 mmol) in THF (12 mL)/methanol (7mL).After 3 h the solution was concentrated, diluted with water (100 mL) andacidified with 10% aqueous HCl. The solid was filtered, washed withwater and triturated with petroleum ether and dried in vacuo to providethe title compound as a white solid (0.645 g, 94%): [a]D25=+14.29° (8.75mg(m CHCl3); NMR (DMSO-d6); δ 8.19 (d, J=8 Hz, 1H), 7.66 (ddd, J=8, 7, 1Hz, 1H), 7.61 (s, 2H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.41 (d, J=8 Hz,1H), 7.38-7.20 (m, 5H), 5.27 (t, J 7 Hz, 1H), 3.37 (dd, 14, 6 Hz, 1H),3.28 (dd, 14, 7 Hz, 1H), 2.43 (s, 3H), 1.59 (s,3H); MS (+FAB): 3 bromineisotope pattern 686 (20%), 688 (75%), 690 (75%), 692 (25%); Anal. Calc.for C29H21Br3O3S: C, 50,53, H, 3.07, N, 0.00. Found: C, 50.04, H, 3.11,N, 0.05.

Example 30

[0264] (R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenoxy]-propanoicacid

[0265] To a solution of2,6-dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenol(0.300 g, 0.554 mmol), commercially available methyl (S)-(−)-lactate(0.079 mL, 0.831 mmol) and triphenylphosphine (0.218 g, 0.831 mmol) indry benzene (5 mL) was added diethyl azodicarboxylate (0.131 mL, 0.831mmol) dropwise at room temperature over a period of 10 minutes under adry nitrogen atmosphere. The reaction mixture was heated at reflux for 4hours and remained stirring at ambient temperature for 24 hours. Thereaction mixture was diluted with diethyl ether and combined with silicagel. The solvents were removed and the adsorbate was flashchromatographed (75/25 petroleum ether/methylene chloride) to provide awhite solid (0.283 g, 81%). To a solution of this solid (0.260 g, 0.415mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added an aqueoussolution of potassium hydroxide (1N, 0.498 mL, 0.498 mmol) dropwise atroom temperature. After stirring 1.5 hours the solvents were removed.The residue was combined with water and acidified with 10% aqueoushydrochloric acid. Diethyl ether was added and after stirring 10 minutesthe two phases were shaken well and separated. The organic phase waswashed with brine, concentrated, and chased with petroleum ether to givetitle compound as a white solid (0.257 g, 99%): mp 224-225° C.; NMR(DMSO-d6); δ 13.09-13.06 (broad s, 1H, COOH), 8.20 (d, J=8 Hz, 1H), 7.75(s, 2H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.55-7.47 (m, 2H), 5.02 (q, J=7Hz, 1H), 2.44 (s, 3H), 1.62 (s, 3H,), 1.56 (d, J=6 Hz, 3H); MS (+FAB):[M+], 3 bromine isotope pattern, 609.7 (30%), 611.8 (75%), 613.8 (100%),615.7 (35%); High resolution MS[(FAB)+ve] Calc Sample mass forC23H17Br3O3S: 609.84485, measured mass 609.85789, mass deviation 13.04mmu. Anal. Calc. for C23H17Br3O3S: C, 45.05, H, 2.79, N, 0.00. Found: C,44.30, H, 2.69, N, 0.38.

Example 31

[0266](S)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid

[0267] Prepared from2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 9) and commercially available (R)-2-hydroxy-4-phenyl-butyrate,ethyl ester according to the procedure of Example 30. White solid: mp176-177° C.; [a] 25/D=+7.58° (10.692 mg/mL, CHCl3); NMR (DMSO-d6); δ13.0 (broad s, 1H, COOH), 8.21 (ddd, J=8, 7 ,1 Hz, 1H), 7.73 (s, 2H),7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.52 (ddd, J=8, 7 , 1 Hz, 1H), 7.46 (m,1H), 7.32-7.28 (m, 2H), 7.24-7.18 (m,3H), 5.03 (t, J=6 Hz, 1H), 2.95 (m,1H), 2.72 (m, 1H), 2.44 (s, 3H), 2.28 (m,2H), 1:61 (s, 3H); MS (+FAB):[M+], 3 bromine isotope pattern, 700 (30%), 702(100%), 704 (75%), 706706(40%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H3.30, N 0.00. Found:C, 51.15, H, 3.13, N, 0.00.

Example 32

[0268](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid

[0269] Prepared from2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 9) and (S)-2-hydroxy-4-phenyl-butyrate, ethyl ester (Example27) according to the procedure of Example 30. White solid: [a]25/D=−12.187° (9.929 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.24 (s, 1H), 8.21 (d,J=8 Hz, 1H), 7.73 (s, 2H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.52-7.45 (m,2H), 7.32-7.28 (m, 2H), 7.24-7.20 (m, 3H) 5.02 (d, J=6Hz, 1H), 2.99-2.86(m, 1H), 2.75-2.65 (m, 1H), 2.45 (s, 3H), 2.30-2.20 (m, 2H), 1.61 (s,3H); MS (+FAB): [M+], 3 bromine isotope pattern, 700 (30%), 702 (100%),704 (90%), 706 (55%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30,N, 0.00. Found: C, 51.33, H, 3.33, N, 0.29.

Example 33

[0270](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid

[0271] Prepared from2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 13) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(Example 25) according to the procedure of Example 30. White solid: opt.rot. [a]25/D=+22.84° (10.068 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.13(broad s, 1H), 8.42 (d, J=8 Hz, 1H), 7.75 (t, J=2 Hz, 2H), 7.58 (ddd,J=8, 7, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.44 (d, J=8 Hz, 1H),7.37-7.19 (m, 7H), 7.15-7.11 (m, 1H), 7.03-7.00 (m, 2H), 5.22 (t, J=7Hz, 1H), 3.37-3.28 (m, 2H), 2.39 (s, 3H), 1.62 (s, 3H); MS (EI): [M+], 2bromine isotope pattern, 716 (10%), 718 (20%), 720 (10%); Anal. Calc.for C35H26Br2O3S2: C, 58.50, H, 3.65, N, 0.00. Found: C, 58.77, H, 3.94,N, 0.16.

Example 34

[0272](R)-2-[2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid

[0273] Prepared from2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 13) and and commercially available methyl (S)-(−)-lactateaccording to the procedure of Example 30. White solid: mp 237-239° C.;[a]25/D=−1.99° (10.051 mg 1 mL, CHCl3); NMR (DMSO-d6); δ 13.2 (broad s,1H, COOH), 8.43 (d, J=8 Hz, 1H), 7.80 (s, 2H), 7.62-7.58 (m, 1H),7.56-7.50 (m, 2H), 7.23-7.13 (m, 3H), 7.04-7.01 (m, 2H), 5.03 (quartet,J=7 Hz, 1H), 2.40 (s, 3H), 1.63 (s, 3H), 1.57 (d, J=8 Hz, 3H); MS (EI):[M+], 2 bromine isotope pattern, 640 (47%), 642 (100%), 644 (56%); Anal.calc. for C29H22Br2O3S2: C, 54.22, H, 3.45, N, 0.00. Found: C, 53.64, H,3.33, N, 0.05.

Example 35

[0274]2-[2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid

[0275] Prepared fromdibromo-4-(9-bromo-3-methyl-2-morpholin-4-yl-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 19) and commercially available methyl (S)-(−)-lactate accordingto the procedure of Example 3Q Yellow solid: Opt. rot. [a]=+26.512°(10.184 mg/mL, DMSO); NMR (pyridine-d5); δ 8.41 (d, J=9 Hz, 1H), 7.84(dd, J=3, 1 Hz, 2H), 7.70 (d, J=7 Hz, 2H), 7.43-7.32 (m, 6H), 5.89 (t,J=7 Hz, 1H), 3.88 (dq, 2H), 3.77 (t, J=7 Hz, 4H), 3.66 (s, 2H), 2.53 (s,4H), 1.70 (s, 3H); MS (+FAB): [(M+H)+], 3 bromine isotope pattern,772(20%), 774 (35%), 776 (45%); HRMS, Calculated sample mass: 771.93674for formula C33H29NO4SBr3 as [M+H]; measured mass: 771.93954, massdeviation 2.80 mmu. Anal. Calc. for C33H28Br3NO4S: C, 51.18, H, 3.64, N,1.81. Found: C, 51.57, H, 3.86, N, 1.73.

Example 36

[0276]2-[2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid

[0277] Prepared fromdibromo-4-(9-bromo-3-methyl-2-morpholin-4-yl-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 19) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(Example 25) according to the procedure of Example 30. Yellow solid:[a]25/D=+13.84° (10.043 mg/mL, DMSO); NMR (pyridine-d5): δ 8.42 (d, J=8Hz, 1H), 7.88 (s, 2H), 7.63 (m, 2H), 7.41 (m, 1H), 5.61 (q, J=4 Hz, 1H),3.78 (t, J=4 Hz, 4H), 3.70-3.63 (m, 3H), 2.56 (s, 4H), 1.97 (d, J=7 Hz,3H), 1.71 (s, 3H); MS (+FAB): [(M+H)+], 3 bromine isotope pattern, 696(35%), 698 (100%), 700 (80%), 702 (40%); Anal. Calc. forC27H24Br3NO4S-HCl: C, 44.14, H, 3.43, N, 1.91. Found: C, 44.94, H, 3.85,N, 1.83.

Example 37

[0278](R)-2-[2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid

[0279] Prepared from2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol(Example 18) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(Example 25) according to the procedure of Example 30. White solid: NMR(DMSO-d6); δ 13.3 (broad band, 1H), 8.20 (d, J=8 Hz, 1H), 7.70(s, 2H),7.66 (ddd, J=8, 7, 1 Hz, 1H), 7.51(ddd, J=8, 7, 1 Hz, 1H), 7.40-7.25(m,6H), 5.21(t, J=7 Hz, 1H), 3.75(s, 2H), 3.32(dd, J=4, 3 Hz, 2H), 2.55 (q,J=7 Hz, 4H), 1.63(s, 3H), 1.02 (t, J=7 Hz, 6H) MS [(+)FAB]: [M+H]+ @ m/z758, 3bromine isotope pattern, 758(25%), 760(80%), 762(75%), 764(35%),689(100%); Anal HPLC, Primesphere 5C-18 column, eluent 62% acetonitrilefor 15 minutes indicated 97.8% purity; High Resolution MS (FAB)+ve:Calculated Sample Mass: 759.95556 for formula C33H31NO3Br3 as [M+H],Measured Mass 759.97370 mass deviation: 18.14 mmu.

Example 38

[0280][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid

[0281] Prepared from of2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol(Example 21) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(Example 25) according to the procedure of Example 30. White solid: mp243-245° C.: NMR (DMSO-d6); δ 11.30 (broad s, 1H), 8.23, 8.22 (2d, J=3Hz, 1H), 8.06, 8.04 (2d, J=3 Hz, 1H), 7.95 (t, J=2, 1H), 7.68 (m, 1H),7.56-7.50 (m, 1H), 7.45 (d, J=8 Hz, 1H),7.34-7.24 (m, 6H), 5.28 5.22(2t, J=6Hz, 1H), 3.40-3.23 (m, 2H), 4.82 (d, J=6 Hz, 1H), 2.46 (s, 3H),1.59 1.57 (2s, 3H); MS (+FAB): 2 bromine isotope pattern 653, 655 , 657;Anal. Calc. for C29H21Br2NO5S: C, 53.15, H, 3.23, N, 2.14. Found: C,53.77, H, 3.73, N, 2.04.

Example 39

[0282]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol

[0283] Step 1

[0284] 2-Isopropyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0285] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3-isopropyl-p-anisic acid (3.0 g, 16.5 mmol,RN-33537-78-9), oxalyl chloride (1.7 mL, 19.5 mmol),N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.0 g,19.8 mmol), tin(IV) chloride (2.1 mL, 18.2 mmol), and anhydrousmethylene chloride (65 mL) the title compound as a dark red oil (6.5 g),which was used without further purification.

[0286] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-isopropyl-4-methoxy-phenyl)-methanone(6.5 g, 17.8 mmol), boron tribromide (9.4 mL, 99 mmol), and methylenechloride (75 mL) the title compound as a yellow solid (1.7 g, 27%): NMR(DMSO-d6): δ 9.49 (s, 1H), 8.42 (s, 1H), 7.94 (d, 1H), 7.47-7.32 (m,3H), 7.01 (s, 1H), 6.93 (s, 2H), 3.32 (m, 1H), 2.39 (s, 3H), 1.59 (s,3H), 1.19 (d, 6H).

[0287] Step 2

[0288] Acetic acid2-isopropyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester

[0289] In a manner similar to the procedure of Example 49, Step 3, therewas obtained from2-isopropyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.5 g,1.4 mmol), acetic anhydride (0.17 mL, 1.8 mmol), and pyridine (3.5 mL)the tile compound as a white solid (0.48 g, 86%): NMR (DMSO-d6): δ 8.49(s, 1H), 8.00-7.96 (d, 1H), 7.48-7.31 (m, 4H), 7.20 (s, 2H), 3.10(septet, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.56 (s, 3H), 1.16 (d, 6H).

[0290] Step3

[0291] Acetic acid2-isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester

[0292] In a manner similar to the procedure of Example 49, Step 4, therewas obtained from acetic acid2-isopropyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester(0.38 g, 0.97 mmol), ferric chloride (8 mg, 0.51 mmol), bromine (0.055mL, 1.1 mmol), and methylene chloride (5 mL) the title compound as awhite solid (0.40, g, 88%): (DMSO-d6): o 8.20 (d, 1H), 7.67-7.62 (m,1H), 7.52-7.43 (m, 2H), 7.34 (d, 1H), 7.22 (m, 2H), 3.09 (septet, 1H),2.43 (s, 3H), 2.37 (s, 3H), 1.54 (s, 3H), 1.16 and 1.15 (two doublets,6H, rotational isomers); MS(EI): [M+], 1 bromine isotope pattern,466/468; Anal. Calc. for C25H23BrO2S: C, 64.24, H, 4.96, N, 0.00. Found:C, 63.84, H, 4.90, N, 0.06.

[0293] Step 4

[0294]2-Isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0295] In a manner similar to the procedure of Example 49, Step 5, therewas obtained from acetic acid2-isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester (0.39 g, 0.83 mmol), aqueous potassium hydroxide (1.0 mL of a 1 Nsolution, 1.0 mmol), tetrahydrofuran (14 mL), and methanol (8.5 mL)there was obtained the title compound as a cream solid (0.35 g, 99%):(DMSO-d6): δ 9.56 (s, 1H), 8.17 (d, 1H), 7.64-7.60 (ddd, 1H), 7.53-7.52(d, 1H), 7.46-7.42 (ddd, 1H), 7.03 (d,1H), 6.97-6.91 (m, 2H), 3.31-3.28(m,1H), 2.42 (s, 3H), 1.58 (s, 3H), 1.16 (d, 6H); MS(EI): [M+], 1bromine isotope pattern, 424/426; Anal. Calc. for C23H21BrOS: C, 64.94,H, 4.98, N, 0.00. Found: C, 64.11, H, 4.99, N, 0.03.

[0296] Step 5

[0297]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol

[0298] To a suspension of2-isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.35 g, 0.81 mmol) and potassium acetate (0.80 g, 8.11 mmol) in glacialacetic acid (11 mL) was added a solution of bromine (0.05 mL, 0.97 mmol)in glacial acetic acid (1.5 mL) dropwise at room temperature. Anadditional 1 mL of acetic acid was used to rinse the pipette and flask.After stirring at room temperature for 4 h the reaction was quenchedwith a small amount of dilute sodium bisulfite and diluted with water(100 mL). The white solid was collected on a sintered glass funnel,washed well with water and dried (Na2SO4) to give the title compound asa white solid (0.40 g,98%): mp 157-162° C.; (DMSO-d6): δ 9.20 (s, 1H),8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.49-7.48 (m, 2H), 7.35 (d, 1H), 7.13(d,1H), 3.40 (septet, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.16 (d, 6H);MS(+FAB): [M+H], 2 bromine isotope pattern, 502 (12%), 504 (30%), 506(18%); Anal. Calc. for C23H20Br2OS: C, 54.78, H, 4.00, N, 0.00. Found:C, 53.67, H; 3.84, N, 0.03.

Example 40

[0299] (R)-2- [2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid

[0300] Step 1

[0301](2R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0302] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol(0.36 g, 0.72 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.19 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol),diethylazodicarboxylate (0.17 mL, 1.1 mmol), and anhydrous benzene (4.0mL) in an oil bath (80° C.) for 4.5 h the title compound as a whitesolid (0.27 g, 56%): (DMSO-d6): δ 8.20 (d, 1H), 7.70-7.60 (m, 1H),7.60-7.40 (m, 2H), 7.40-7.20 (m, 7H), 5.07 and 4.95 (two triplets, 1H,rotational isomers), 3.60 and 3.56 (two s, 3H, rotational isomers),3.40-3.20 (m, 3H), 2.45 and 2.43 (two singlets, 3H, rotational isomers),1.59 and 1.53 (two singlets, 3H, rotational isomers), 1.20-1.00 (m, 6H).

[0303] Step 2

[0304](2R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid

[0305] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.26 g, 0.52 mmol), aqueous potassium hydroxide (1.1mL of a 1 N solution, 1.1 mmol), tetrahydrofuran (6 mL), and methanol (2mL) the title compound as a white solid (0.23 g, 68%): Opt. Rot.[a]25/D=+38.90 (9.970 mg/mL, CHCl3); (DMSO-d6): δ 13.1 (broad s, 1H),8.19 (d, 1H), 7.68-7.62 (m, 1H), 7.53-7.44 (m, 2H), 7.40-7.38 (m, 1H),7.35-7.30 (m, 4H), 7.29-7.23 (m, 2H), 5.00 (m, 1H), 3.55 (septet, 1H),3.35 (m, 2H), 2.42 and 2.43 (two singlets, 3H, rotational isomers), 1.57and 1.52 (two singlets, 3H, rotational isomers), 1.14-1.03 (m, 6H);MS(+FAB): [M+], 2 bromine isotope pattern, 650 (15%), 652 (30%), 654(21%); Anal. Calc. for C32H28Br2O3S: C, 58.91, H, 4.33, N, 0.00. Found:C, 58.72, H, 4.45, N, 0.10.

Example 41

[0306](R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid

[0307] Step 1

[0308](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0309] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.30 g,0.87 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.62 g,3.5 mmol), triphenylphosphine (0.91 g, 3.5 mmol),diethylazodicarboxylate (0.54 mL, 3.5 mmol), and anhydrous benzene (7.0mL) in an oil bath (85° C.) for 18 h the title compound as a yellow oil(0.18 g, 41%): (DMSO-d6): δ 8.40 (s, 1H), 7.90 (d, 1H), 7.50-7.20 (m,6H), 7.20-7.00 (m, 3H), 7.00-6.80 (m, 2H), 5.20 (t,1H), 3.65 and 3.63(two s, 3H, rotational isomers), 3.30-3.20 (m, 3H), 2.40 (s, 3H), 1.50(s, 3H), 1.15 (two doublets, 3H, rotational isomers), 1.05 (twodoublets, 3H, rotational isomers).

[0310] Step 2

[0311](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid

[0312] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.18 g, 0.35 mmol), aqueous potassium hydroxide (0.71mL of a 1 N solution, 0.71 mmol), tetrahydrofuran (6 mL), and methanol(2 mL) the title compound as a white solid (0.072 g, 41%): (DMSO-d6): δ13.10 (broad s, 1H), 8.43 (d, 1H), 7.49 (dd, 1H), 7.46-7.29 (m, 7H),7.28-7.22 (m, 1H), 7.10-7.03 (m, 2H), 6.89-6.85 (m, 1H), 5.07 (m, 1H),3.40-3.19 (m, 3H), 2.38 and 2.37 (two singlets, 3H, rotational isomers),1.53 and 1.51 (two singlets, 3H, rotational isomers), 1.15 and 1.14 (twodoublets, 3H, rotational isomers), 1.03 (d, 3H); MS(EI): [M+] 494; Anal.Calc. for C32H30O3S: C, 77.70, H, 6.11, N, 0.00. Found: C, 75.71, H,6.29, N, 0.03.

Example 42

[0313](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid (WAY-143461)

[0314] Step 1

[0315] 2-Sec-butyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0316] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3-sec-butyl-p-anisic acid (3.0 g, 14.4 mmol, preparedby the method of M. Derenberg and P. Hodge, Tetrahedron Lett. 1971,3825-3828; D. G. Davies, et al., J. Chem. Soc. (C) 1971, 455-460),oxalyl chloride (1.4 mL, 15.8 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylthiophene (3.5 g, 16.6 mmol), tin(IV) chloride (1.5mL, 15.8 mmol), and anhydrous methylene chloride (92 mL) an oil (6.2 g),which was used without further purification.

[0317] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-sec-butyl-4-methoxy-phenyl)-methanone(6.2 g, 15.8 mmol), boron tribromide (7.1 mL, 74.8 mmol), and methylenechloride (54 mL) the title compound as a solid (2.34 g, 41%): MS(EI):[M+] 360.

[0318] Step 2

[0319]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenol

[0320] In a manner similar to the procedure of Example 39, Step 6, therewas obtained from2-sec-butyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.34 g,6.5 mmol), bromine (0.69 mL, 13 mmol), potassium acetate (6.4 g, 65mmol), and glacial acetic acid (65 mL) the title compound as a solid(0.63 g, 19%): MS(EI): [M+], 2 bromine isotope pattern, 516 (50%), 518(100%), 520 (55%).

[0321] Step 3

[0322](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid

[0323] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenol(0.63 g, 1.2 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.44 g, 2.4 mmol), triphenylphosphine (0.64 g, 2.4 mmol),diethylazodicarboxylate (0.38 mL, 2.4 mmol), and anhydrous benzene (2.4mL) at room temperature for 5 days an oil (0.60 g, 72%), which was usedwithout further purification.

[0324] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.55 g, 0.73 mmol), aqueous potassium hydroxide (1.6mL of a 1 N solution, 1.6 mmol), tetrahydrofuran (7.5 mL), and methanol(2.5 mL) the title compound as a foam (0.26 g, 48%): MS(EI): [M+], 2bromine isotope pattern, 664 (14%), 666 (26%), 668 (14%); Anal. Calc.for C33H30Br2O3S: C, 59.47, H, 4.54, N, 0.00. Found: C, 59.44, H, 4.81,N, 0.03.

Example 43

[0325](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid

[0326] Step 1

[0327](2-Benzyl-415-dimethyl-thiophen-3-yl)-(3-ethyl-4-methoxy-phenyl)-methanone

[0328] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3-ethyl-p-anisic acid (5.0 g, 27.7 mmol,RN-22934-35-6), oxalyl chloride (2.7 mL, 30.5 mmol),N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (6.7 g,33.2 mmol), tin(IV) chloride (3.6 mL, 30.5 mmol), and anhydrousmethylene chloride (177 mL) the title compound as an oil (5.2 g, 51%):(DMSO-d6): δ 7.59-7.54 (m, 2H), 7.25-7.11 (m, 3H), 7.09-7.04 (m, 3H),3.87 (s, 3H), 3.84 (s, 2H), 2.57 (q, 2H), 2.26 (s, 3H), 1.82 (d, 3H),1.10 (t, 3H); MS(+FAB): [M+H] 365; Anal. Calc. for C23H24O2S: C, 75.79,H, 6.64, N, 0.00. Found: C, 75.34, H, 6.72, N, 0.00.

[0329] Step 2

[0330] 2-Ethyl -4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0331] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-ethyl-4-methoxy-phenyl)-methanone(6.1 g, 16.7 mmol), boron tribromide (7.1 mL, 75.4 mmol), and methylenechloride (58 mL) the title compound as a solid (2.6 g, 46%): (DMSO-d6):o 9.49 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.47 (d, 1H), 7.43 (m, 1H),7.33 (m, 1H), 7.02-6.90 (m containing a singlet at δ 6.94, 3H),2.73-2.52 (complex m, ABX pattern, 2H, rotational isomers), 2.40 (s,3H), 1.62 (s, 3H), 1.15 (t, 3H); MS(EI): [M+] 332.

[0332] Step 3

[0333] (R)-2-[2-Bromo-4-(9-bromo-23-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0334] In a manner similar to the procedure of Example 39, Step 6, therewas obtained from2-ethyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen4-yl)-phenol (2.6 g, 7.8mmol), bromine (0.83 mL, 15.7 mmol), potassium acetate (7.7 g, 78.5mmol), and glacial acetic acid (78 mL) the title compound as a solid(0.73 g), which was used without further purification.

[0335] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenol(0.73 g, 1.5 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.54 g, 3.0 mmol), triphenylphosphine (0.78 g, 3.0 mmol),diethylazodicarboxylate (0.47 mL, 3.0 mmol), and anhydrous benzene (3.0mL) at room temperature for 5 days an oil (0.58 g, 60%): (DMSO-d6): δ8.19 (d, 1H), 7.65 (m, 1H), 7.54-7.22 (m containing a singlet at δ 7.32,9H), 5.09 and 5.01 (two t, 1H, rotational isomers), 3.60 and 3.56 (twos, 3H, rotational isomers), 3.45-3.25 (complex m, 2H, rotationalisomers), 2.78-2.50 (complex m, ABX pattern, 2H), 2.42 and 2.43 (two s,3H, rotational isomers), 1.59 and 1.54 (two s, 3H, rotational isomers),1.09 and 1.07 (two t, 3H, rotational isomers).

[0336] Step 4

[0337](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid

[0338] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.41 g, 0.63 mmol), aqueous potassium hydroxide (1.3mL of a 1 N solution, 1.3 mmol), tetrahydrofuran (4.5 mL), and methanol(1.5 mL) the title compound as a pale yellow solid (0.38 g, 95%):(DMSO-d6): δ 13.05 (br s, 1H), 8.20 (d, 1H), 7.65 (m, 1H), 754-7.18 (m,9H), 5.05 (m, 1H), 3.33 (m, 2H), 2.90-2.50 (complex m, ABX pattern, 2H),2.43 and 2.41 (two s, 3H, rotational isomers), 1.58 and 1.53 (two s, 3H,rotational isomers), 1.10 and 1.09 (two t, 3 H, rotational isomers);MS(−ESI): [M−H], 2 bromine isotope pattern, 635 (44%), 637 (100%), 639(62%); Anal. Calc. for C31H26Br2O3S: C, 58.32, H, 4.11, N, 0.00. Found:C, 58.11, H, 4.32, N, 0.18.

Example 44

[0339](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid

[0340] Step 1

[0341](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0342] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-isopropyl-phenol(0.26 g, 0.67 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.32 g, 1.8 mmol), triphenylphosphine (0.46 g, 1.8 mmol),diethylazodicarboxylate (0.28 mL, 1.8 mmol), and anhydrous benzene (7.0mL) in an oil bath (90° C.) for 4.5 h the title compound as a whitesolid (0.15 g, 38%): (DMSO-d6): δ 8.18 (m, 1H), 7.66-7.58 (m, 1H),7.50-7.40 (m, 2H), 7.40-7.30 (m,4H), 7.30-7.20 (m, 1H), 7.14-7.04 (m,2H), 6.92-6.87 (m, 1H), 5.27 (t, 1H), 3.70 and 3.65 (two singlets, 3H,rotational isomers), 3.40-3.20 (m, 3H), 2.40 (s, 3H), 1.49 (s, 3H), 1.15and 1.13 (two doublets, 3H, rotational isomers), 1.06 and 1.04 (twodoublets, 3H, rotational isomers).

[0343] Step 2

[0344](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid

[0345] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.50mL of a 1 N solution, 0.50 mmol), tetrahydrofuran (6 mL), and methanol(2 mL) the title compound as a white solid (0.14 g, 95%): (DMSO-d6): δ13.14 (broad s, 1H), 8.18-8.15 (m, 1H), 7.64-7.58 (m, 1H), 7.48-7.31 (m,6H), 7.30-7.22 (m, 1H), 7.11-7.04 (m, 2H), 6.90-6.85 (m, 1H), 5.07(m,,1H). 3.39-3.18 (m, 3H), 2.41 and 2.40 (two singlets, 3H, rotationalisomers), 1.51 and 1.49 (two singlets, 3H, rotational isomers), 1.15 and1.14 (two doublets, 3H, rotational isomers), 1.04 and 1.03 (twodoublets, 3H, rotational isomers); MS(EI): [M+], 1 bromine isotopepattern, 572/574; Anal. Calc. for C32H29BrO3S: C, 67.01, H, 5.10, N,0.00. Found: C, 67.19, H, 5.47, N, 0.03.

Example 45

[0346](R)-2-[2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid

[0347] Step 1

[0348](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone

[0349] To a slurry of 3-cyclopentyl-p-anisic acid (5.0 g, 22.7 mmol,RN-59216-82-9) in anhydrous methylene chloride (60 mL) was added oxalylchloride (2.4 mL, 27.2 mmol) and N,N-dimethylformamide (2 drops) at roomtemperature under nitrogen. After stirring for 1.5 h the reactionmixture was concentrated under reduced pressure. The residue wasdissolved in carbon disulfide (32 mL) and the resulting solution wasadded to 2,3-dimethyl-5-benzylthiophene (5.1 g, 25.0 mmol). At −78° C.under nitrogen, tin(IV) chloride (2.9 mL, 25.0 mmol) was added, and thereaction mixture was then stirred at room temperature for 4 h. Thesolution was poured onto a mixture of ice and water (200 mL) andextracted with diethyl ether (200 mL). The diethyl ether layer waswashed twice with sodium bicarbonate (50 mL) and once with brine (50mL). Concentration under reduced pressure and chromatography withpetroleum ether:ethyl acetate (95:5) gave the title compound as an amberoil (4.8 g, 52%): (DMSO-d6): δ 7.61-7.54 (m, 2H), 7.24-7.14 (m, 3H),7.08-7.02 (m, 3H), 3.87 (s, 3H), 3.84 (s, 2H), 3.42-3.30 (m, 1H), 2.26(s, 3H), 2.00-1.85 (m, 2H), 1.81 (s, 3H), 1.74-1.58 (m, 4H), 1.48-1.36(m, 2H); MS(EI): [M+] 404; Anal. Calc. for C26H28O2S: C, 77.19, H, 6.98,N, 0.00. Found: C, 76.26, H, 7.24, N, 0.04.

[0350] Step 2

[0351] 2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0352] To(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone(4.8 g, 11.7 mmol) in anhydrous methylene chloride (70 mL) at −78° C.under nitrogen was added dropwise over a period of 20 min borontribromide (3.6 mL, 37.6 mmol). The reaction mixture was then allowed tostir at room temperature for 22 h. The solution was poured onto amixture of ice and water (600 mL) and extracted with diethyl ether (800mL). The diethyl ether layer was washed twice with water (500 mL) andonce with brine (500 mL). Concentration under reduced pressure andchromatography with petroleum ether:ethyl acetate (97:3) gave the titlecompound as a white solid (3.4 g, 78%): mp 156-158° C.; (DMSO-d6): o9.48 (s, 1H), 8.42 (s, 1H), 7.93 (d, 1H), 7.46-7.41 (m, 2H), 7.35-7.30(m, 1H), 7.00 (s, 1H), 6.95-6.90 (m, 2H), 3.38-3.28 (m, 1H), 2.39 (s,3H), 1.99-1.90 (m, 2H), 1.68-1.47 (m, 6H), 1.60 (s, 3H); MS(EI): [M+]372; Anal. Calc. for C25H24OS: C, 80.60, H, 6.49, N, 0.00. Found: C,80.39, H, 6.43, N, 0.04.

[0353] Step 3

[0354](R)-2-[2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester

[0355] In a manner similar to the procedure of Example 49f, there wasobtained from2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.40g, 1.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.29g, 1.6 mmol), triphenylphosphine (0.42 g, 1.6 mmol),diethylazodicarboxylate (0.25 mL, 1.6 mmol), and anhydrous benzene (6.0mL) in an oil bath (80° C.) for 6 h the title compound as a white solid(0.26 g, 46%): (DMSO-d6): δ 8.44 (s, 1H), 7.94 (d, 1H), 7.43-7.26 (m,8H), 7.08-7.01 (m, 2H), 6.88-6.85 (m, 1H), 5.24 (dd,1H), 3.70 and 3.66(two singlets, 3H, rotational isomers), 3.42-3.20 (m, 3H), 2.38 (s, 3H),2.02-1.30 (m containing a singlet at δ 1.52, 11H).

[0356] Step 4

[0357](R)-2-[2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid

[0358] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester (0.22 g, 0.41 mmol), aqueous potassium hydroxide (0.82mL of a 1 N solution, 0.82mmol), tetrahydrofuran (12 mL), and methanol(4 mL) the title compound as a white solid (0.21 g, 95%): Opt. Rot.[a]25/D=−8.19° (8.549 mg/mL, CHCl3); (DMSO-d6): δ 13.10 (broad s, 1H),8.43 (d, 1H), 7.93 (m, 1H), 7.43-7.20 (m, 8H), 7.07-7.02 (m, 2H),6.88-6.84 (m, 1H), 5.03 and 5.07 (two dd, 1H, rotational isomers),3.39-3.17 (m, 3H), 2.38 and 2.37 (two singlets, 3H, rotational isomers),1.90 (m, 1H), 1.76 (m, 1H), 1.70-1.32 (m containing two singlets at δ1.54 and 1.52 (rotational isomers), 9H); MS(EI): [M+] 520; Anal. Calc.for C34H32O3S: C, 78.43, H, 6.19, N, 0.00. Found: C, 77.96, H, 6.40, N,0.02; Analytical HPLC indicates a major component (96.9%).

Example 46

[0359](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0360] Step 1

[0361](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid acid methyl ester

[0362] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (0.40g, 1.2 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.49g, 2.7 mmol), triphenylphosphine (0.71 g, 2.7 mmol),diethylazodicarboxylate (0.36 mL, 2.7 mmol), and anhydrous benzene (13mL) in an oil bath (70-86° C.) for 10 h the title compound as a whitesolid (0.24 g, 40%): (DMSO-d6): δ 8.44 (s, 1H), 7.94 (d, 1H), 7.45-7.39(m, 2H), 7.35-7.30 (m, 5H), 7.28-7.24 (m, 1H), 6.96 (s, 2H), 4.77 (t,1H), 3.56 (s,3H), 3.34-3.25 (m, 2H), 2.39 (s, 3H), 2.22 (s, 3H), 2.17(s, 3H), 1.56 (s, 3H); MS(EI): [M+] 494; Anal. Calc. for C32H30O3S: C,77.70, H, 6.11, N, 0.00. Found: C, 76.53, H, 5.85, N, 0.08.

[0363] Step 2

[0364](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0365] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.23 g, 0.46 mmol), aqueous potassium hydroxide (0.91mL of a 1 N solution, 0.91 mmol), tetrahydrofuran (12 mL), and methanol(4 mL) the title compound as a white solid (0.19 g, 86%): Opt. Rot.[a]25/D=+33.04° (10.170 mg/mL, MeOH); (DMSO-d6): δ 12.9 (broad s, 1H),8.44 (s, 1H), 7.94 (d, 1H), 7.45-7.40 (m, 2H), 7.35-7.22 (m, 6H), 6.95(s, 2H), 4.70 (t, 1H), 3.25 (d, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 2.22(s, 3H), 1.56 (s, 3H); MS(EI): [M+] 480; Anal. Calc. for C31H28O3S: C,77.47, H, 5.87, N, 0.00. Found: C, 76.23, H, 5.77, N, 0.03; AnalyticalHPLC indicates a major component (94.6%).

Example 47

[0366]R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0367] Step 1

[0368] Acetic acid2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester

[0369] To2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (2.8g, 7.5 mmol) in anhydrous pyridine (20 mL) at room temperature undernitrogen was added dropwise acetic anhydride (0.92 mL, 9.8 mmol). Thereaction mixture was placed in the refrigerator. After 41 h the reactionwas diluted and acidified with 10% aqueous hydrochloric acid to a pHof 1. The mixture was extracted with diethyl ether (500 mL), and thediethyl ether layer was washed with 5% aqueous hydrochloric acid (100mL), twice with water (100 mL), brine (100 mL), and then dried (MgSO4).Concentration under reduced pressure gave the tide compound as a whitesolid (3.1 g, 98%): (DMSO-d6): δ 8.48 (s, 1H), 7.97 (d, 1H), 7.47-7.43(m, 1H), 7.38-7.36 (m, 2H), 7.28 (s, 1H), 7.19 (d, 2H), 3.14 (quintet,1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.99-1.91 (m, 2H), 1.69-1.40 (m, 6H),1.56 (s, 3H); MS(EI): [M+] 414; Anal. Calc. for C27H26O2S: C, 78.23, H,6.32, N, 0.00. Found: C, 77.68, H, 6.39, N, 0.04.

[0370] Step 2

[0371] Acetic acid2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester

[0372] To acetic acid2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester(2.9 g, 7.7 mmol) in anhydrous methylene chloride (68 mL) was addedferric chloride (66 mg, 0.41 mmol). The reaction mixture was placedunder nitrogen and cooled to −78° C. The reaction mixture was protectedfrom light and a solution of bromine (0.44 mL, 8.5 mmol) in anhydrousmethylene chloride (11 mL) was added dropwise over a period of 15 min.After stirring at −78° C. for 45 min the reaction was quenched withdilute sodium bisulfite, and then poured into water (200 mL). Theresulting mixture was extracted with diethyl ether (300 mL), and thediethyl ether layer was washed with water and then brine. Concentrationunder reduced pressure and chromatography with petroleum ether:ethylacetate (95:5) gave the title compound as a white solid (2.7 g, 79%):(CDCl3): δ 8.28 (d, 1H), 7.58-7.52 (m, 2H), 7.39-7.34 (m, 1H), 7.29 (d,1H), 7.18 (dd, 1H), 7.14 and 7.13 (d, 1H), 3.18 (quintet, 1H), 2.44 (s,3H), 2.40 (s, 3H), 2.06-2.02 (m, 2H), 1.75-1.45 (in containing a singletat δ 1.60, 9H); MS(EI): [M+], 1 bromine isotope pattern, 492/494; Anal.Calc. for C27H25BrO2S: C, 65.72, H, 5.11, N, 0.00. Found: C, 63.18, H,4.96, N, 0.00.

[0373] Step 3

[0374]2-Cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0375] To acetic acid2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester (2.7 g, 5.4 mmol) in tetrahydrofuran (88 mL) and methanol (30 mL)at room temperature was added dropwise an aqueous potassium hydroxide(6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h the reaction mixturewas concentrated under reduced pressure. The resulting residue wascombined with water (200 mL) and acidified with 10% aqueous hydrochloricacid to a pH of 1. The solution was extracted with diethyl ether (300mL) and the diethyl ether layer was washed twice with water and dried(Na2SO4). Concentration under reduced pressure gave the title compoundas a white solid (2.4 g, 100%): (DMSO-d6): δ 9.54 (s, 1H), 8.16 (d, 1H),7.61 (m, 1H), 7.52 (s, 1H), 7.43 (m, 1H), 7.03 (s, 1H), 6.93 (m, 2H),3.32 (m, 1H), 2.41 (s, 3H), 1.94 (m, 2H), 1.58 (s, 3H), 1.72-1.42 (m,6H); MS(EI): [M+], 1 bromine isotope pattern, 450/452; Anal. Calc. forC25H23BrOS: C, 66.52, H, 5.13, N, 0.00. Found: C, 67.17, H, 5.25, N,0.04.

[0376] Step 4

[0377](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0378] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenol(0.40 g, 0.89 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.48 g, 2.7 mmol), triphenylphosphine (0.70 g, 2.7 mmol),diethylazodicarboxylate (0.42 mL, 2.7 mmol), and anhydrous benzene (6mL) in an oil bath (85° C.) for 4.5 h the title compound as a whitesolid (0.19 g, 34%): NMR (DMSO-d6): δ 8.17 (d, 1H), 7.64-7.59 (m, 1H),7.45-7.40 (m, 2H), 7.38-7.24 (m, 5H), 7.10-7.03 (m, 2H), 6.90-6.86 (m,1H), 5.28-5.24 (m, 1H), 3.70 and 3.66 (two singlets, 3H, rotationalisomers), 3.40-3.24 (m, 3H), 2.40 (s, 3H), 1.95-1.30 (m, 8H), 1.49 (s,3H); MS(EI): [M+], 1 bromine isotope pattern, 612/614.

[0379] Step 5

[0380](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0381] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.18 g, 0.30 mmol), aqueous potassium hydroxide (0.39mL of a 1 N solution, 0.39 mmol), tetrahydrofuran (6 mL), and methanol(2 mL) the title compound as a white solid (0.15 g, 84%): NMR (DMSO-d6):δ 13.12 (broad s, 1H), 8.18-8.15 (m, 1H), 7.64-7.58 (m, 1H), 7.47-7.22(m, 7H), 7.10-7.04 (m, 2H), 6.89-6.86 (m, 1H), 5.10-5.03 (m, 1H),3.32-3.18 (m, 3H), 2.40 (s, 3H), 1.90 (m, 1H), 1.76 (m, 1H), 1.70-1.30(m containing two singlets at δ 1.51 and 1.50 (rotational isomers), 9H);MS(−ESI): [M−H], 1 bromine isotope pattern, 597/599; Anal. Calc. forC34H31BrO3S: C, 68.11, H, 5.21, N, 0.00. Found: C, 68.10, H, 5.31, N,0.01.

Example 48

[0382](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid (

[0383] Step 1

[0384]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenol

[0385] To a suspension of2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(2.0 g, 4.4 mmol) and potassium acetate (4.4 g, 44.3 mmol) in glacialacetic acid (60 mL) was added dropwise over a period of 17 minutes asolution of bromine (0.27 mL, 5.3 mmol) in glacial acetic acid (8 mL).The thick reaction mixture was diluted with glacial acetic acid (20 mL).After stirring at room temperature for 2 h the reaction mixture waspoured into water (500 mL). The solution was extracted once with diethylether (250 mL), and then with diethyl ether (100 mL). The combinedextracts were washed twice with water (100 mL). Concentration underreduced pressure and chromatography with petroleum ether:ethyl acetate(98:2), followed by trituation with petroleum ether gave the titlecompound as a white solid (1.2 g, 52%): mp 189.5-191° C.; (DMSO-d6): δ9.19 (s, 1H), 8.18 (d, 1H), 7.65-7.61 (m, 1H), 7.50-7.47 (m, 2H), 7.33(d, 1H), 7.11 (d, 1H), 3.42 (quintet, 1H), 2.43 (s, 3H), 2.00-1.97 (m,2H), 1.69-1.46 (m, 6H), 1.60 (s, 3H); MS(EI): [M+], 2 bromine isotopepattern, 528 (46%), 530 (100%), 532 (52%); Anal. Calc. for C25H22Br2OS:C, 56.62, H, 4.18, N, 0.00. Found: C, 55.78, H, 4.12, N, 0.05.

[0386] Step 2

[0387](2R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0388] To a solution of2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-cyclopentyl-phenol(1.2 g, 2.2 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.60 g, 3.3 mmol), and triphenylphosphine (0.87 g, 3.3 mmol) inanhydrous benzene (20 mL) at room temperature under nitrogen was addeddropwise diethylazodicarboxylate (0.52 mL, 3.3 mmol). After 5 h at roomtemperature the reaction mixture was adsorbed onto silica gel andchromatographed with petroleum ether:ethyl acetate (95:5) to yield thetitle compound as a white solid (1.2 g, 86%): mp 167-168.5° C.; NMR(CDCl3): δ 8.28 (m, 1H), 7.58-7.47 (m, 2H), 7.41-7.36 (m, 2H), 7.34-7.25(m, 5H), 7.18 (m, 1H), 5.11 and 5.02 (two dd, 1H, rotational isomers),3.66 and 3.63 (two s, 3H, rotational isomers), 3.58-3.33 (m, 3H), 2.44and 2.43 (two s, 3H, rotational isomers), 2.20 (m, 1H), 1.95 (m, 1H),1.75-1.32 (m containing two singlets at δ 1.63 and 1.69 (rotationalisomers), 9H); MS(EI): [M+], 2 bromine isotope pattern, 690 (46%), 692(100%), 694 (54%); Anal. Calc. for C35H32Br2O3S: C, 60.70, H, 4.66, N,0.00. Found: C, 60.31, H, 4.64, N, 0.01.

[0389] Step 3

[0390](2R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0391] To a solution of(2R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-cyclopentyl-phenoxy]-3-phenyl-propionicacid methyl ester (1.0 g, 1.5 mmol) in tetrahydrofuran (30 mL) andmethanol (10 mL) at room temperature was added dropwise aqueouspotassium hydroxide (3.0 mL of a 1 N solution, 3.0 mmol). After 4 h thereaction mixture was concentrated under reduced pressure. The residuewas taken up in water (100 mL) and acidified with aqueous 10%hydrochloric acid. After stirring for 15 min the solid was filtered andwashed with water:methanol (95:5). The solid was dried under a vacuum at50° C. for 18 h to yield the title compound as a white solid (0.99 g,100%): Opt. Rot. [a]25/D=+38.44° (9.624 mg/mL, MeOH); NMR (DMSO-d6): δ13.01 (broad s, 1H), 8.19 (d, 1H), 7.67-7.62 (m, 1H), 7.54-7.22 (m, 9H),4.92 (m, 1H), 3.46 (m, 1H), 3.34 (m, 2H), 2.42 and 2.41 (two singlets,3H, rotational isomers), 1.99 (m, 1H), 1.98 (m, 1H), 1.72-1.27 (mcontaining two s at δ 1.57 and 1.53 (rotational isomers), 6H); MS(−ESI):[M−H], 2 bromine isotope pattern, 675 (72%), 677 (100%), 679 (66%);Anal. Calc. for C34H30Br2O3S: C, 60.19, H, 4.46, N, 0.00. Found: C,59.53, H, 4.35, N, −0.04.

Example 49

[0392](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0393] Step 1

[0394](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3,5-dimethyl-phenyl)-methanone

[0395] To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol,RN-21553-46-8) in anhydrous methylene chloride (200 mL) at roomtemperature under nitrogen was added oxalyl chloride (9.6 mL, 110 mmol)and N,N-dimethylformamide (5 drops). After two hours the solvent wasremoved. The resulting residue was dissolved in anhydrous methylenechloride (200 mL), and added to 2,3-dimethyl-5-benzylthiophene (17.1 g,84.4 mmol) under nitrogen. The resulting mixture was, cooled to −78° C.,and tin(IV) chloride (10.8 mL, 92.8 mmol) was added quickly. The −78° C.bath was removed and the mixture was stirred at room temperature for 2h. The reaction mixture was then poured onto ice water (1 L), and theresulting mixture was extracted once with diethyl ether (700 mL), and asecond time with diethyl ether (400 mL). The combined diethyl etherextracts were washed with ice water(500 mL), dilute sodium bicarbonate(500 mL), water (500 mL), brine (mL), and then dried (Na2SO4).Concentration under reduced pressure gave the title compound as a yellowoil (25.2 g, 82%): NMR (DMSO-d6): δ 7.40 (s, 2H), 7.24-7.15 (m, 3H),7.06 (d, 2H), 3.83 (s, 2H), 3.70 (s, 3H), 2.28 (s, 3H), 2.26 (s, 6H),1.83 (s, 3H).

[0396] Step 2

[0397] 4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol

[0398](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3,5-dimethyl-phenyl)-methanone(25.2 g, 69.2 mmol) in anhydrous methylene chloride (420 mL) was placedunder nitrogen and cooled to −78C. Boron tribromide (20.9 mL, 221 mmol)was added dropwise over a period of 16 min, and the resulting mixturewas stirred at −78C for 1.5 h. The −78C bath was removed and thereaction mixture was stirred at room temperature for 4 h. The reactionmixture was then poured onto ice water (IL) containing some sodiumbisulfite, and the resulting mixture was extracted once with diethylether (1 L), and a second time with diethyl ether (300 mL). The combineddiethyl ether extracts were washed twice with water (1 L), brine (1L),and then dried (Na2SO4). Concentration under reduced pressure afforded adark residue which was combined with a second run done on(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3,5-dimethyl-phenyl)-methanone(13.9 g, 38.1 mmol) and boron tribromide (11.5 mL, 122 mmol). Adsorptiononto silica gel and chromatography with petroleum ether:ethyl acetate(90:10) gave a thick foamy amber residue identified as2,6-dimethyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (24.0g, 67%): NMR (DMSO-d6): δ 8.41 (s, 2H), 7.93 (d, 1H), 7.49-7.39 (m, 2H),7.34-7.28 (m, 1H), 6.87 (s, 2H), 2.38 (s, 3H), 2.23 (s, 6H), 1.62 (s,3H); MS(EI): [M+] 332.

[0399] Step 3

[0400] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester

[0401] To a solution of4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (24.0g, 72.2 mmol) in pyridine (200 mL) at 0C under nitrogen was addeddropwise acetic anhydride (8.9 mL, 93.9 mmol) over a period of 10 min.After 45 min at 0C, the reaction mixture was placed in the freezer for18 h, then removed and stirred for 2 h in an ice bath that was allowedto warm to room temperature. The reaction mixture was poured onto water(1 L) and acidified with 10% hydrochloric acid to a pH of 1. Theresulting mixture was extracted with diethyl ether (1 L), which waswashed with 10% hydrochloric acid (1 L), twice with water (1 L), brine(700 mL), and dried (MgSO4). Concentration under reduced pressure andchromatography with petroleum ether:ethyl acetate (97:3) gave the titlecompound as a cream solid (22.4 g, 79%): NMR (CDCl3): δ 8.26 (s, 1H),7.87 (d, 1H), 7.58 (d, 1H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.07(s, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 2.23 (s, 6H), 1.67 (s, 3H); MS(EI):[M+] 374; Anal. Calc. for C24H22O2S: C, 76.97, H, 5.92, N, 0.00. Found:C, 76.17, H, 5.75, N, 0.22.

[0402] Step 4

[0403] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester

[0404] A solution of acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenyl ester(10.0 g, 26.7 mmol) and ferric chloride (0.23 g, 1.4 mmol) in anhydrousmethylene chloride (231 mL) was placed at −78C under nitrogen. Thereaction mixture was protected from light and a solution of bromine (1.5mL, 29.4 mmol) in anhydrous methylene chloride (38 mL) was addeddropwise over a period of 50 min. After 30 min the reaction was quenchedwith dilute sodium bisulfite, diluted with water, and the resultingmixture was extracted with diethyl ether. The diethyl ether layer waswashed twice with water, brine, and then dried (MgSO4). Concentrationunder reduced pressure and chromatography with petroleum ether:ethylacetate (97:3, then 95:5) gave the title compound as a white solid (6.7g, 55%): NMR (DMSO-d6): δ 8.27 (d, 1H), 7.60 (d, 1H), 7.56-7.52 (ddd,1H), 7.38-7.34 (ddd, 1H), 7.06 (s, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 2.22(s, 6H), 1.64 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 452/454;Anal. Calc. for C24H21BrO2S: C, 63.58, H, 4.67, N, 0.00. Found: C,63.41, H, 4.45, N, 0.08.

[0405] Step 5

[0406]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl1-phenol

[0407] To a solution of acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester (6.5 g, 14.3 mmol) in tetrahydrofuran (240 mL) and methanol (80mL) at room temperature was added dropwise aqueous potassium hydroxide(17.2 mL of a 1N solution, 17.2 mmol). After 4 h at room temperature thereaction mixture was placed in the freezer for 18 h. The reaction wasremoved from the freezer and allowed to stir at room temperature. Moreaqueous potassium hydroxide (41.5 mL of a 1N solution, 41.5 mmol),tetrahydrofuran (50 mL), and methanol (10 mL) were added. The mixturewas diluted with water (500 mL), acidified with 1N aqueous solution ofhydrochloric acid, and extracted with diethyl ether. The diethyl etherlayer was washed twice with water (500 mL), and dried (MgSO4).Concentration under reduced pressure gave a residue which was adsorbedonto silica gel. Chromatography with petroleum ether:ethyl acetate(97:3, then 95:5) gave the title compound as a white foamy solid (5.5 g,93%): NMR (CDCl3): δ 8.41 (s, 1H), 8.16 (d, 1H), 7.64-7.54 (m, 2H),7.46-7.40 (m, 1H), 6.89 (s, 2H), 2.41 (s, 3H), 2.23 (s, 6H), 1.60 (s,3H); MS(−ESI): [M−H], 1 bromine isotope pattern, 409/411.

[0408] Step 6

[0409](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]3-phenyl-propionicacid methyl ester

[0410] To a solution of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol(5.0 g, 12.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(3.3 g, 18.3 mmol), and triphenylphosphine (4.8 g, 18.3 mmol) inanhydrous benzene (50 mL) at room temperature under nitrogen was addeddropwise diethyl azodicarboxylate (2.6 mL, 18.3 mmol) over a period of25 min. The reaction mixture was heated for 2 h, then stirred at roomtemperature for 3 days. The crude reaction mixture was adsorbed ontosilica gel and chromatographed twice with petroleum ether:ethyl acetate(95:5) to yield the title compound as a white foamy solid (4.5 g, 65%):NMR (DMSO-d6): δ 8.18 (d, 1H), 7.64 (ddd, 1H), 7.53-7.43 (m, 2H),7.38-7.24 (m, 5H), 7.00 (s, 2H), 4.80 (t, 1H), 3.58 (s, 3H), 3.31 (m,2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 (s, 3H); MS(EI):[M+], 1 bromine isotope pattern, 572/574; Anal. Calc. for C32H29BrO3S:C, 67.01, H, 5.10, N, 0.00. Found: C, 66.33, H, 5.09, N, 0.09;Analytical HPLC indicates a major component (94.39%).

[0411] Step 7

[0412](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0413] To a solution of(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester (3.1 g, 5.4 mmol) in tetrahydrofuran (125 mL) andmethanol (41 mL) at room temperature was added dropwise aqueouspotassium hydroxide (6.5 mL of a 1N solution, 6.5 mmol). After 1.5 h atroom temperature the reaction mixture was placed in the freezer for 18h. The reaction was removed from the freezer and allowed to stir at roomtemperature. More aqueous potassium hydroxide (19.5 mL of a 1N solution,19.5 mmol) was added, and the reaction mixture was allowed to stir atroom temperature for 9.5 h. Concentration under reduced pressure gave aresidue which was diluted with water (1 L). The aqueous layer wasacidified with concentrated hydrochloric acid to a pH of 1, andextracted with diethyl ether (700 mL). The diethyl ether layer waswashed twice with water (500 mL), and then dried (Na2SO4). Concentrationunder reduced pressure and chromatography on silica gel (treated with 2%phosphoric acid in methanol) with petroleum ether:ethyl acetate (90:10,then 86:14) gave the title compound as a white solid foam (1.9 g, 64%):Opt. Rot. [a]25/D=+33.380 (10.035 mg/mL, MeOH); NMR (DMSO-d6): δ 12.90(broad singlet, 1H), 8.17 (d, 1H), 7.63 (ddd, 1H), 7.50-7.43 (m, 2H),7.36-7.23 (m, 5H), 6.97 (s, 2H), 4.71 (t, 1H), 3.25 (d, 2H), 2.41 (s,3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.54 (s, 3H); MS(EI): [M+], 1 bromineisotope pattern, 558/560; Anal. Calc. for C31H27BrO3S: C, 66.55, H,4.86, N, 0.00. Found: C, 65.91, H, 5.05, N, 0.09; Analytical HPLCindicates a major component (99.5%).

Example 50

[0414](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid

[0415] Step 1

[0416](2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone

[0417] In a manner similar to the procedure of Example-49, Step 1, therewas obtained from 3,5-diisopropyl-p-anisic acid (5.0 g, 21.2 mmol,RN-117439-59-5), oxalyl chloride (2.2 mL, 25.4 mmol),N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylthiophene (4.3 g,21.2 mmol), tin(IV) chloride (5.0 mL, 42.7 mmol), and anhydrousmethylene chloride (82 mL) the title compound as a yellow oil (4.1 g,45%): NMR (DMSO-d6): δ 7.47 (s, 2H), 7.23-7.12 (m, 3H), 7.02-6.99 (m,2H), 3.86 (s, 2H), 3.73 (s, 3H), 3.31-3.20 (m, 2H), 2.27 (s, 3H), 1.82(s, 3H), 1.15 (d, 12H); MS(EI): [M+] 420.

[0418] Step 2

[0419]2,6-Diisopropyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0420] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3,5-diisopropyl-4-methoxy-phenyl)-methanone(4.3 g, 10.1 mmol), boron tribromide (3.1 mL, 32.4 mmol), and methylenechloride (60 mL) the title compound as a yellow foam (1.2 g, 30%): NMR(DMSO-d6): δ 8.42 (s, 1H), 8.24 (s, 1H), 7.94 (d, 1H), 7.48-7.32 (m,3H), 6.90 (s, 2H), 3.45-3.35 (m, 2H), 2.38 (s, 3H), 1.57 (s, 3H), 1.15(d, 12H); MS(−ESI): [M−H] 387.

[0421] Step 3

[0422](2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0423] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenol (0.33 g,0.84 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.5 g,8.3 mmol), triphenylphosphine (2.2 g, 8.3 mmol), diethylazodicarboxylate(1.3 mL, 8.3 mmol), and anhydrous benzene (9.0 mL) in an oil bath (85°C.) for 18 h the title compound as an oil (0.11 g, 24%): NMR (DMSO-d6):δ 8.45 (s, 1H), 7.96 (d, 1H), 7.50-7.25 (m, 8H), 7.03 (s, 2H), 4.54 (t,1H), 3.56 (s, 3H), 3.40-3.18 (m, 4H), 2.38 (s, 3H), 1.51 (s 3H), 1.14and 1.13 (two doublets, 6H, rotational isomers), 1.07 and 1.04 (twodoublets, 6H, rotational isomers); MS(EI): [M+] 550.

[0424] Step 4

[0425](2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid

[0426] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.11 g, 0.20 mmol), aqueous potassium hydroxide (0.39mL of a 1 N solution, 0.39 mmol), tetrahydrofuran (3 mL), and methanol(1 mL) the title compound as a white solid (0.10 g, 98%): NMR (DMSO-d6):δ 12.97 (broad s, 1H), 8.46 (s, 1H), 7.96 (d, 1H), 7.47-7.25 (m, 8H),7.04 (s, 2H), 4.47 (t, 1H), 3.41-3.30 (m, 2H), 3.28-3.23 (m, 2H), 2.40(s, 3H), 1.53 (s, 3H), 1.15 (d, 6H), 1.08 (d, 6H); MS(EI): [M+] 536;Anal. Calc. for C35H36O3S: C, 78.32, H, 6.76, N, 0.00. Found: C, 77.12,H, 6.86, N, −0.11; Analytical HPLC indicates a major component (93.2%).

Example 51

[0427] (R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid

[0428] Step 1

[0429](2-Benzyl-4.5-dimethyl-thiophen-3-yl)-(3-fluoro-4-methoxy-phenyl)-methanone

[0430] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3-fluoro-p-anisic acid (10.0 g, 58.8 mmol), oxalylchloride (6.2 mL, 71.0 mmol), N,N-dimethylformamide (12 drops),2,3-dimethyl-5-benzylthiophene (11.9 g, 58.8 mmol), tin(IV) chloride(10.3 mL, 88.0 mmol), and anhydrous methylene chloride (130 mL) thetitle compound as a yellow solid (7.53 g, 68%): MS(+ESI): [M+H] 355;Anal. Calc. for C21H19FO2S: C, 71.16, H, 5.40, N, 0.00. Found: C, 70.01,H, 5.43, N, −0.06.

[0431] Step 2

[0432] 2-Fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0433] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(3-fluoro-4-methoxy-phenyl)-methanone(7.5 g, 21.2 mmol), boron tribromide (7.0 mL, 74.3 mmol), and methylenechloride (88 mL) the title compound as a yellow foam (6.7 g, 99%):MS(EI): [M+] 322; Anal. Calc. for C20H15FOS: C, 74.51, H, 4.69, N, 0.00.Found: C, 73.96, H, 4.94, N, −0.08.

[0434] Step 3

[0435](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid

[0436] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from2-fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.0 g, 3.1mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.67 g, 3.7mmol), triphenylphosphine (0.98 g, 3.7 mmol), diethylazodicarboxylate(0.59 mL, 3.7 mmol), and anhydrous benzene (20 mL) in an oil bath (85°C.) for 5 h the title compound as a white solid (0.86 g), which was usedwithout further purification.

[0437] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from (2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid methyl ester (0.86 g, 1.8 mmol), aqueous potassium hydroxide (3.6mL of a 1 N solution, 3.6 mmol), tetrahydrofuran (12 mL), and methanol(4 mL) the title compound as a white solid (0.41 g, 63%): Opt. Rot.[a]25/D=+0.87° (11.473 mg/mL, MeOH); MS(EI): [M+] 470; Anal. Calc. forC29H23FO3S: C, 74.02, H, 4.93, N, 0.00. Found: C, 73.95, H, 5.22, N,0.12.

Example 52

[0438](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid

[0439] Step 1

[0440] Acetic acid2-fluoro-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester

[0441] In a manner similar to the procedure of Example 49, Step 3, therewas obtained from2-fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.0 g, 3.1mmol), acetic anhydride (0.36 mL, 3.8 mmol), and pyridine (7.5 mL) ayellow solid (1.1 g), which was used without further purification.

[0442] In a manner similar to the procedure of Example 49, Step 4, therewas obtained from acetic acid2-fluoro-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester (1.1g, 2.9 mmol), ferric chloride (24.8 mg, 0.15 mmol), bromine (0.16 mL,3.2 mmol), and methylene chloride (12 mL) the title compound as a yellowoil (0.86 g, 67%): MS(EI): [M+], 1 bromine isotope pattern, 442/444.

[0443] Step 2

[0444]2-Fluoro-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol

[0445] In a manner similar to the procedure of Example 49, Step 5, therewas obtained from acetic acid2-fluoro-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester (0.29 g, 0.65 mmol), aqueous potassium hydroxide (0.79 mL of a 1 Nsolution, 0.79 mmol), tetrahydrofuran (12 mL), and methanol (7.5 mL)there was obtained the tide compound as an off-white solid (0.3 g,100%): MS(EI): [M+], 1 bromine isotope pattern, 400/402.

[0446] Step 3

[0447](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid methyl ester

[0448] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from2-Fluoro-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.29 g, 0.72 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.19 g, 1.1 mmol), triphenylphosphine (0.28 g, 1.1 mmol),diethylazodicarboxylate (0.17 mL, 1.1 mmol), and anhydrous benzene (5.0mL) the tide compound as a white solid (0.23 g, 58%): MS(EI): [M+], 1bromine isotope pattern, 562/564.

[0449] Step 4

[0450](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid

[0451] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid methyl ester (0.23 g, 0.41 mmol), aqueous potassium hydroxide (0.50mL of a 1 N solution, 0.50 mmol), tetrahydrofuran (6 mL), and methanol(2 mL) the title compound as a white solid (0.17 g, 74%): MS(EI): [M+],1 bromine isotope pattern, 548/550; Anal. Calc. for C29H22BrFO3S: C,63.39, H,4.04, N, 0.00. Found: C, 62.14, H, 4.29, N, 0.16; AnalyticalHPLC indicates a major component (82.5%).

Example 53

[0452] [4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-acetic acid

[0453] Step 1

[0454] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2.6-diisopropyl-phenylester

[0455] In a manner similar to the procedure of Example 49, Step 3, therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (5.0g, 13.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol), and pyridine (85mL) the tile compound as a white solid (5.37 g, 91%): mp 243-245° C.;NMR (DMSO-d6): δ 8.49 (s, 1H), 7.98 (d, 1H), 7.49-7.39 (m, 3H), 7.16 (s,2H), 3.01 (septet, 2H), 2.43 (s, 3H), 2.41 (s, 3H), 1.56 (s, 3H), 1.16(d, 12H); MS(EI): [M+] 430; Anal. Calc. for C28H30O2S: C, 78.10, H,7.02, N, 0.00. Found: C, 77.95, H, 7.04, N, 0.07; Analytical HPLCindicates a major component (99.3%).

[0456] Step 2

[0457] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2.6-diisopropyl-phenylester

[0458] In a manner similar to the procedure of Example 49, Step 4, therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenylester (0.80 g, 18.5 mmol), ferric chloride (16 mg, 0.1 mmol), bromine(0.13 mL, 2.6 mmol), and methylene chloride (19 mL) the title compoundas a white solid (0.53 g, 56%): NMR (DMSO-d6): δ 8.21 (d, 1H), 7.68-7.62(m, 1H), 7.60-7.42 (m, 2H), 7.18 (s, 2H), 3.00 (septet, 2H), 2.42 (s,6H), 1.53 (s, 3H), 1.14 (d, 12H).

[0459] Step 3

[0460]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol

[0461] In a manner similar to the procedure of Example 49, Step 5, therewas obtained from acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenylester (0.52 g, 1.0 mmol), aqueous potassium hydroxide (1.64 mL of a 1 Nsolution, 1.6 mmol), tetrahydrofuran (18.5 mL), and methanol (11.5 mL)there was obtained the title compound as a cream solid (0.45 g, 95%): mp212-216° C.; NMR (DMSO-d6): δ 8.30 (s, 1H), 8.17 (d, 1H), 7.61 (ddd,1H), 7.53 (d, 1H), 7.44 (ddd, 1H), 6.92 (s, 2H ), 3.41 (septet, 2H),2.41 (s, 3H), 1.55 (s, 3H), 1.15 (d, 12H); MS(EI): [M+], 1 bromineisotope pattern, 466/468; Anal. Calc. for C26H27BrOS: C, 66.80, H, 5.82,N, 0.00. Found: C, 66.17, H, 5.63, N, 0.06

[0462] Step 4

[0463] [4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-acetic acid methyl ester

[0464] A solution of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol(0.42 g, 0.89 mmol), methyl bromoacetate (0.36 mL, 3.8 mmol), andpotassium carbonate (0.42 g, 3.0 mmol) in anhydrousN,N-dimethylformamide (3.5 mL) at room temperature under nitrogen wasstirred for 2 days. The reaction mixture was diluted with water andextracted with diethyl ether. Concentration under reduced pressure andchromatography with petroleum ether:ethyl acetate (95:5) gave the titlecompound as a white solid (0.42 g, 87%): NMR (DMSO-d6): δ 8.20 (d, 1H),7.66-7.61 (m, 1H), 7.48 (d, 2H), 7.11 (s, 2H), 4.56 (s, 2H), 3.77 (s,3H), 3.42-3.27 (m, 2H), 2.42 (s, 3H), 1.51 (s, 3H), 1.18 and 1.16 (twodoublets, 12H).

[0465] Step 5

[0466] [4-(9-Bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-acetic acid

[0467] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid methyl ester (0.40 g, 0.74 mmol), aqueous potassium hydroxide (0.89mL of a 1 N solution, 0.89 mmol), tetrahydrofuran (6 mL), and methanol(2 mL) the title compound as a white solid (0.37 g, 95%): mp 228-231° C.NMR (DMSO-d6): δ 12.98 (broad s, 1H), 8.19 (d, 1H), 7.65-7.61 (m,1H),7.47 (d, 2H), 7.10 (s, 2H), 4.44 (s, 2H), 3.40 (septet, 2H), 2.41 (s,3H), 1.51 (s, 3H), 1.18 and 1.16 (two doublets, 12H); MS(EI): [M+], 1bromine isotope pattern, 524/526; Anal. Calc. for C28H29BrO3S: C, 64.00,H, 5.56, N, 0.00. Found: C, 63.32, H, 5.39, N, 0.01; Analytical HPLCindicates a major component (96%).

Example 54

[0468](2R)-2-[2,6-Dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid

[0469] Step 1

[0470](2-Benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3,5-dibromo-phenyl)-methanone

[0471] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3,5-dibromo-p-anisic acid (8.0 g, 25.8 mmol), oxalylchloride (2.48 mL, 28.4 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylfuran (5.77 g, 31.0 mmol), tin(IV) chloride (3.30mL, 28.4 mmol), and anhydrous methylene chloride (165 mL) the titlecompound as a solid (2.92 g, 24%): (DMSO-d6): δ 7.81 (s, 2H), 7.28-7.14(m, 3H), 7.04 (d, 2H), 3.86 (s, 3H), 3.84 (s, 2H), 2.19 (s, 3H), 1.81(s, 3H); MS(EI): [M+], 2 bromine isotope pattern, 476 (25%), 478 (50%),480 (25%).

[0472] Step 2

[0473] 4-(2,3 -Dimethyl-naphtho[23 -b]furan-4-yl)-2,6-dibromo-phenol

[0474] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3,5-dibromo-phenyl)-methanone(2.52 g, 5.30 mmol), boron tribromide (3.79 mL, 40.0 mmol), andmethylene chloride (18 mL) the title compound (0.93 g), which was usedwithout further purification: (DMSO-d6): δ 10.19 (br s, 1H), 8.01 (d,1H), 7.98 (s, 1H), 7.56 (s, 2H), 7.51 (d, 1H), 7.44 (ddd, 1H), 7.36(ddd, 1H), 2.39 (s, 3H), 1.62 (s, 3H); MS(−ESI): [M−H], 2 bromineisotope pattern, 443 (63%), 445 (100%), 447 (63%).

[0475] Step 3

[0476](2R)-2-[2,6-Dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester

[0477] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-dibromo-phenol(0.88 g, 1.97 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.71 g, 3.94 mmol), triphenylphosphine (1.03 g, 3.94 mmol),diethylazodicarboxylate (0.62 mL, 3.94 mmol), and anhydrous benzene (3.9mL) at room temperature the title compound as a solid (1.15 g, 96%): NMR(DMSO-d6): δ 8.04 (d, 1H), 8.03 (s, 1H), 7.71 (s, 2H), 7.51-7.24 (m,8H), 5.11 (dd, 1H), 3.63 (s, 3H), 3.53-3.35 (two overlapping quartets,ABX pattern, 2H), 2.41 (s, 3H), 1.60 (s, 3H); MS(EI): [M+], 2 bromineisotope pattern, 606 (52%), 608 (100%), 610 (52%).

[0478] Step 4

[0479](2R)-2-[2,6-Dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid

[0480] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester (0.25 g, 0.41 mmol), aqueous potassium hydroxide (0.82mL of a 1 N solution, 0.82 mmol), tetrahydrofuran (3.0 mL), and methanol(1.0 mL) the title compound as a white solid (0.24 g, 100%): NMR(DMSO-d6): δ 13.11 (br s, 1H), 8.02 (d, 1H), 8.01 (s, 1H), 7.66 (s, 2H),7.49-7.21 (m, 8H), 5.19 (t, 1H), 3.36 (d, 2H), 2.39 (s, 3H), 1.58 (s,3H); MS(EI): [M+], 2 bromine isotope pattern, 592 (50%), 594 (100%), 596(50%); Anal. Calc. for C29H22Br2O4: C, 58.61, H, 3.73, N, 0.00. Found:C, 58.52, H, 4.01, N, 0.05.

Example 55

[0481](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2.3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid

[0482] Step 1

[0483](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0484] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol(0.46 g, 0.98 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.70 g, 3.9 mmol), triphenylphosphine (1.02 g, 3.9 mmol),diethylazodicarboxylate (0.62 mL, 3.9 mmol), and anhydrous benzene (1.0mL) in an oil bath (90° C.) for 24 h the title compound as a white solid(0.20 g, 32%): NMR (DMSO-d6): δ 8.19 (d, 1H), 7.65-7.60 (m, 1H),7.50-7.40 (m, 2H), 7.38-7.27 (m, 5H), 7.06 (s, 2H), 4.55 (t, 1H), 3.55(s, 3H), 3.35-3.19 (m, 4H), 2.41 (s, 3H), 1.49 (s, 3H), 1.13 (d, 6H),1.06 and 1.04 (two doublets, 6H, rotational isomers).

[0485] Step 2

[0486](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid

[0487] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.20 g, 0.31 mmol), aqueous potassium hydroxide (1.2mL of a 1 N solution, 1.2 mmol), tetrahydrofuran (3 mL), and methanol (1mL) the title compound as a white solid (0.18 g, 93%): mp 222-226° C.;NMR (DMSO-d6): δ 13.0 (broad s, 1H), 8.20 (d, 1H), 7.64 (ddd, 1H),7.48-7.46 (m, 2H), 7.38-7.27 (m, 5H), 7.06 (s, 2H), 4.48 (t, 1H),3.40-3.26 (m, 4H), 2.42 (s, 3H), 1.50 (s, 3H), 1.14 (d, 6H), 1.07 (d,6H); MS(−ESI): [M−H], 1 bromine isotope pattern, 558/560; Anal. Calc.for C35H35BrO3S: C, 68.28, H, 5.73, N, 0.00. Found: C, 68.15, H, 5.83,N, 0.03; Analytical HPLC indicates a major component (100%).

Example 56

[0488][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-hydroxy-phenyl]-carbamicAcid tert-Butyl Ester

[0489] A solution of2-amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.382 g, 0.801 mmol) and di-t-butyl dicarbonate (0.191 g, 0.875 mmol)in THF (0.83 mL) was heated at 70° C. for 15 h. The reaction mixture wasdiluted with ether and silica gel was added. The ether was removed andthe adsorbate was flash chromatographed (9:1 pet. ether:ethyl acetate)to provide the title compound as a white solid (0.447 g, 97%): mp205-207° C.: NMR (DMSO-d6); 9.61 (s, 1H), 8.55 (2, 1H). 8.19 (d, J=8 Hz,1H), 7.65 (ddd, J=8, 6, 2 Hz, 1H), 7.52-7.46 (m, 3 H), 7.27 (d, J=2 Hz,1H), 2.44 (d, J=1 Hz, 3H), 1.67 (d, J=1 Hz, 3H), 1.40 (s, 9 H); MS (EI):2 bromine isotope pattern 575 (20%, M+), 577 (50%, M+), 579 (20%, M+),519 (50%, M+H-tBu), 521 (100%, M+H-tBu), 523 (55%, M+H-tBu); Anal. Calc.for C25H23Br2NO3S: C, 52.01, H, 4.02, N, 2.43. Found: C, 51.09, H, 3.84,N, 2.28.

Example 57

[0490]9-Bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene

[0491] Iodomethane (0.22 mL, 3.55 mmol) and potassium carbonate (0.490g, 3.55 mmol) were added to a stirred, room temperature solution of9-bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene(0.600 g, 1.183 mmol) in DMF (8 mL). After 7 h, more iodomethane (0.1mL, 1.61 mmol) was added and the suspension was stirred an additional 17h. The reaction mixture was added to water and ectracted with ether.Silica gel was added. The ether was removed and the adsorbate was flash,chromatographed (95:5 pet. ether:ethyl acetate) to provide the titlecompound as a yellow solid (0.416 g, 67%): mp 204-205° C.: NMR(DMSO-d6); 8.23 (d, J=8 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 8.04 (d, J=2 Hz,1H), 7.69 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 6, 1 Hz, 1H), 7.47(d, J=8 Hz, 1H), 4.05 (s, 3H), 2.45 (d, J=1 Hz, 3H), 1.62 (d, J=1 Hz,3H); MS (FAB+): 2 bromine isotope pattern 519, 521, 523; Anal. Calc. forC21H15Br2NO3S: C, 48.39, H, 2.90, N, 2.69. Found: C, 48.16, H, 2.69, N,2.58.

Example 58

[0492]3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine

[0493] A stirred suspension of9-bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene(0.372, 0.714 mmol), tin (II) dichloride (805 mg, 3.57 mmol) and ethylacetate (4 mL)was heated to 70° C. where disolution occured. After 30min, the reaction mixture was cooled to room temperature, diluted withethyl acetate and silica gel was added. The ethyl acetate was removedand the adsorbate was flash chromatographed (4:1 pet. ether:ethylacetate) to provide the title compound as a white solid (0.324 g, 92%):mp 198-200° C.: NMR (DMSO-d6); 8.18 (d, J=8 Hz, 1H), 7.64 (ddd, J=8, 6,1 Hz, 1H), 7.58 (d, J=8 Hz, 1H), 7.50 (ddd, J=8, 6, 1 Hz, 1H), 6.70 (d,J=2 Hz, 1H), 6.64 (d, J=2 Hz, 1H), 5.46 (s, 1H), 3.80 (s, 3H), 2.44 (d,J=1 Hz, 3H), 1.73 (d, J=1 Hz, 3H); MS (EI): 2 bromine isotope pattern489 (50%, M+), 491 (100%, M+), 493 (60%, M+); Anal. Calc. forC21H17Br2NOS: C, 51.34, H, 3.49, N, 2.85. Found: C, 51.00, H, 3.43, N,2.71.

Example 59

[0494][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticAcid Methyl Ester

[0495] Methyl bromoacetate (0.285 mL, 3.01 mmol) was added to a stirred,room temperature suspension of3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine(0.260 g, 0.529 mmol) and potassium carbonate (0.411 g, 3.00 mmol) inDMF (1.7 mL). After two days, more methyl bromoacetate (0.135 mL, 1.5mmol) and the reaction mixture was stirred for a day longer. Thereaction mixture was added to water and the solid was filtered andwashed with water. The solid was triturated with pet. ether and dried at60° C. under vacumm to provide the title compound as a white solid(0.212 g, 71%): mp 194-198° C.: NMR (DMSO-d6); 8.17 (dd, J=8, 1 Hz, 1H),7.63 (ddd, J=8, 6, 1 Hz, 1H), 7.53-7.45 (m, 2H), 6.77 (d, J=2 Hz, 1H),6.54 (d, J=2 Hz, 1H), 6.10 (t, J=7 Hz, 1H), 3.97 (dd, J=7, 4 Hz, 2H),3.83 (s, 3H), 3.52 (s, 3H),2.43 (s, 3H), 1.69 (s, 3H); MS (FAB+): 2bromine isotope pattern 561, 563, 565; Anal. Calc. for C24H21Br2NO3S: C,51.17, H, 3.76, N, 2.49. Found: C, 50.43, H, 3.63, N, 2.53.

Example 60

[0496][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticAcid

[0497] Aqueous potassium hydroxide (1N, 0.64 mL, 0.64 mmol)was added toa stirred room temperature solution of[3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid methyl ester (0.180 g, 0.320 mmol) in THF (2.5 mL), methanol (1.5mL). After 4 h, the solvent was removed and water was added. Thesuspension was acidified and extracted with ether. Silica gel was added.The ether was removed and the adsorbate was flash chromatographed(Gradient: 7:3pet. ether:ethyl acetate to ethyl acetate to 9:1 ethylacetate:methanol) to provide the title compound as a white solid (0.112g, 64%): mp>190° C. (dec): NMR (DMSO-d6); 8.16 (d, J=8 Hz, 1H), 7.63(ddd, J=8, 6, 1 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 7.48 (ddd, J=8, 6, 1 Hz,1H), 6.72 (d, J=2 Hz, 1H), 6.43 (d, J=2 Hz, 1H), 5.74 (broad s, 1H),3.83 (s, 3H), 3.46 (s, 2H), 2.42 (s, 3H), 1.71 (s, 3H); MS (FAB+): 2bromine isotope pattern 547, 549, 551; Anal. Calc. for C23H19Br2NO3S: C,50.29, H, 3.49, N, 2.55. Found: C, 49.54, H, 3.73, N, 2.26.

Example 61

[0498](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid

[0499] Step 1

[0500](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3,5-diethyl-phenyl)-methanone

[0501] In a manner similar to the procedure of Example 49, Step 1, therewas obtained from 3,5-diethyl-p-anisic acid (9.45 g, 45.4 mmol, preparedby the method of J. Lipowitz and T. Cohen, J. Org. Chem. 1965, 30,3891-3894; C. K. Bradsher. et a; J. Am. Chem. Soc. 1954, 76, 2357-2362;C. K. Bradsher. et. al; Org. Prep. Proced. Int., 1986, 18, 2213-2215),oxalyl chloride (4.4 mL, 49.9 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylthiophene (11.0 g, 54.5 mmol), tin(IV) chloride(5.8 mL, 49.9 mmol), and anhydrous methylene chloride (291 mL) the titlecompound as an oil (17.7 g, 99%): (DMSO-d6): δ 7.43 (s, 2H), 7.24-7.11(m, 3H), 7.07-7.01 (m, 2H), 3.85 (s, 2H), 3.70 (s, 3H), 2.62 (q, 4H),2.26 (s, 3H), 1.83 (s, 3H), 1.14 (t, 6H).

[0502] Step2

[0503] 4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol

[0504] In a manner similar to the procedure of Example 49, Step 2, therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3,5-diethyl-phenyl)-methanone(17.67 g, 45.0 mmol), boron tribromide (12.8 mL, 135.4 mmol), andmethylene chloride (90 mL) the title compound (16.6 g), which was usedwithout further purification: (DMSO-d6): δ 8.41 (s, 1H), 8.31 (s, 1H),7.93 (d, 1H), 7.47 (d, 1H), 7.42 (ddd, 1H), 7.32 (ddd, 1H), 6.86 (s,2H), 2.76-2.56 (complex m, ABX pattern, 4H), 2.39 (s, 3H), 1.60 (s, 3H),1.14 (t, 6H); MS(+ESI): [M]+ 360.

[0505] Step 3

[0506] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenyl ester

[0507] In a manner similar to the procedure of Example 49, Step 3, therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol (16.6 g,46.0 mmol), acetic anhydride (5.66 mL, 59.9 mmol), pyridine (92 mL), andmethylene chloride (92 mL) a residue, which was trituated withacetone:hexane (1:1) to give the title compound as a solid (6.85 g,37%): NMR (DMSO-d6): δ 8.47 (s, 1H), 7.97 (d, 1H), 7.49-7.34 (m, 3H),7.11 (s, 2H), 2.60-2.46 (m, 4H), 2.40 (two overlapping s, 6H), 1.59 (s,3H), 1.13 (t, 6H); MS(+ESI): [M+H] 403; Anal. Calc. for C26H26O2S: C,77.57, H, 6.51, N, 0.00. Found: C, 76.46, H, 6.60, N, 0.19.

[0508] Step4

[0509] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenylester

[0510] In a manner similar to the procedure of Example 49, Step 4, therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenyl ester(1.0 g, 2.5 mmol), ferric chloride (20 mg, 0.12 mmol) bromine (2.7 mL,2.7 mmol), and methylene chloride (25 mL) the title compound as a solid(1.2 g, 100%): NMR (DMSO-d6): δ 8.20 (d, 1H), 7.68-7.61 (m, 1H), 7.49(d, 2H), 7.13 (s, 2H), 2.60-2.47 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H),1.56 (s, 3H), 1.13 (t, 6H); MS(+APCI): [M+H], 1 bromine isotope pattern,481/483; Anal. Calc. for C26H25BrO2S: C, 64.86, H, 5.23, N, 0.00. Found:C, 63.06, H, 5.13, N, 0.03.

[0511] Step 5

[0512]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol

[0513] In a manner similar to the procedure of Example 49, Step 5, therewas obtained from acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenylester (1.0 g, 2.1 mmol), aqueous potassium hydroxide (2.5 mL of a 1 Nsolution, 2.5 mmol), tetrahydrofuran (29.7 mL), and enough methanol tocreate a homogeneous solution the title compound as a solid (0.83 g,91%): NMR (DMSO-d6): δ 8.36 (s, 1H), 8.16 (d, 1H), 7.61 (ddd, 1H), 7.55(d, 1H), 7.44 (ddd, 1H), 6.88 (s, 2H), 2.76-2.56 (complex m, ABXpattern, 4H), 2.41 (s, 3H), 1.58 (s, 3H), 1.14 (t, 6H); MS(+APCI):[M+H], 1 bromine isotope pattern, 439/441.

[0514] Step 6

[0515](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0516] In a manner similar to the procedure of Example 49, Step 6, therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol(0.83 g, 1.89 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(2.72 g, 15.0 mmol), triphenylphosphine (3.96 g, 15.0 mmol),diethylazodicarboxylate (2.36 mL, 15.0 mmol), and anhydrous benzene (40mL) at room temperature the title compound as a solid (0.74 g, 65%): NMR(DMSO-d6): δ 8.18 (d, 1H), 7.66-7.60 (m, 1H), 7.48-7.44 (m, 2H),7.37-7.23 (m, 5H), 7.01 (s, 2H), 4.69 (t, 1H), 3.55 (s, 3H), 3.29 (m,2H), 2.74-2.45 (m, 4H), 2.41 (s, 3H), 1.53 (s, 3H), 1.09 and 1.08 (twot, 6H); MS(+APCI): [M+H], 1 bromine isotope pattern, 601/603.

[0517] Step 7

[0518](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid

[0519] In a manner similar to the procedure of Example 49, Step 7, therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.70 g, 1.16 mmol), aqueous potassium hydroxide (2.3mL of a 1 N solution, 2.3 mmol), tetrahydrofuran (11.6 mL), and enoughmethanol to create a homogeneous solution a solid. Recrystallizationfrom hexane/acetone gave the title compound as a white solid (0.15 g,22%): NMR (DMSO-d6): δ 12.91 (br s, 1H), 8.18 (d, 1H), 7.63 (ddd, 1H),7.51-7.42 (m, 2H), 7.36-7.22 (m, 5H), 7.00 (s, 2H), 4.62 (t, 1H), 3.25(d, 2H), 2.74 (complex m, ABX pattern, 1H), 2.66 (complex m, ABXpattern, 2H), 2.55 (complex m, ABX pattern, 1H), 2.41 (s, 3H), 1.53 (s,3H), 1.10 (t, 6H); MS(−ESI): [M−H], 1 bromine isotope pattern, 585/587;Anal. Calc. for C33H31BrO3S: C, 67.46, H, 5.32, N, 0.00. Found: C,66.84, H, 5.24, N, 0.03.

Example 62

[0520]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0521] A mixture of(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid (0.5 g, 0.89 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.34 g, 1.77 mmol), glycine ethyl ester hydrochloride(0.24 g, 1.72 mmol), potassium carbonate (0.50 g, 3.62 mmol), andmethylene chloride (6 mL) was stirred at room temperature. After threedays the reaction was diluted with methylene chloride, washed twice withwater, once with brine, and then dried (Na2SO4). Adsorption onto silicagel and chromatography with hexane:ethyl acetate (75:25) gave a solid(0.4 g), which was treated with potassium hydroxide (1.11 mL of a 1Nsolution, 1.11 mmol), tetrahydrofuran (8.9 mL), and enough methanol tocreate a homogeneous solution. After 24 h at room temperature thereaction mixture was diluted with diethyl ether, washed once with 1Naqueous hydrochloric acid, twice with water, once with brine, and thendried (Na2SO4). Concentration under reduced pressure andrecrystallization from hexane/ethyl acetate gave a white solid (0.20 g,36%): NMR (DMSO-d6): δ 12.58 (br s, 1H), 8.53 (t, 1H), 8.18 (d, 1H),7.64 (ddd, 1H), 7.52-7.43 (m, 2H), 7.34-7.19 (m, 5H), 6.92 (s, 2H), 4.87(t, 1H), 3.88-3.70 (two overlapping quartets, ABX pattern, 2H),3.31-3.10 (two overlapping quartets, ABX pattern, 2H), 2.43 (s, 3H),2.23 (s, 3H), 2.19 (s, 3H), 1.56 (s, 3H); MS(+APCI): [M+H], 1 bromineisotope pattern, 616/618; Anal. Calc. for C33H30BrNO4S: C, 64.29, H,4.90, N, 2.27. Found: C, 63.97, H, 4.48, N, 2.03.

Example 63

[0522]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0523] A mixture of(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid (0.48 g, 0.82 mmol), oxalyl chloride (0.071 mL, 0.81 mmol), andbenzene (16.3 mL) was stirred at room temperature for 40 min. Glycineethyl ester hydrochloride (0.14 g, 1.0 mmol) and potassium carbonate(0.36, 2.6 mmol) was added, and the resulting slurry was allowed to stirat room temperature overnight. The reaction mixture was adsorbed ontosilica gel and chromatographed with hexane:ethyl acetate (90:10) to givea solid (0.17 g), which was treated with potassium hydroxide (1.32 mL ofa 1N solution, 1.32 mmol), tetrahydrofuran (10 mL), and enough methanolto create a homogeneous solution. After stirring at room temperature forapproximately 30 min, the reaction mixture was diluted with diethylether, washed once with 1N aqueous hydrochloric acid, once with water,once with brine, and then dried (Na2SO4). The solution was concentratedunder reduced pressure, dissolved in methylene chloride, and dried(Na2SO4). Concentration under reduced pressure gave a white solid (0.14g, 26%): NMR (DMSO-d6): δ 12.51 (br s, 1H), 8.49 (t, 1H), 8.17 (d, 1H),7.62 (ddd, 1H), 7.46 (d, 2H), 7.32-7.17 (m, 5H), 6.95 (s, 1H), 6.94 (s,1H), 4.73 (t, 1H), 3.85-3.68 (two overlapping quartets, ABX pattern,2H), 3.30-3.10 (two overlapping quartets, ABX pattern, 2H), 2.80-2.50(complex m, ABX pattern, 4H), 2.41 (s, 3H), 1.54 (s, 3H), 1.06 (t, 6H);MS(−ESI): [M−H], 1 bromine isotope pattern, 642/644; Anal. Calc. forC35H34BrNO4S: C, 65.21, H, 5.32, N, 2.17. Found: C, 65.03, H, 5.36, N,2.07.

Example 64

[0524](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid Step 1

[0525] (2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester

[0526] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (5.13 g,13.4 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (4.8 g,26.6 mmol), triphenylphosphine (7.0 g, 26.7 mmol),diethylazodicarboxylate (4.2 mL, 26.7 mmol), and anhydrous benzene (74mL) at room temperature the tide compound as a solid (4.8 g, 66%): NMR(DMSO-d6): δ 8.17 (d, J=8 Hz, 1H), 7.62 (ddd, J=1, 6, 8 Hz, 1H),7.50-7.20 (m containing a doublet at δ 7.22 (J=8 Hz), , 9H), 7.01 (d,J=8 Hz, 2H), 5.25 (dd, J=5, 7 Hz, 1H), 3.67 (s, 3H), 3.25 (complex m,ABX pattern, 2H), 2.41 (s, 3H), 1.51 (s, 3H); MS(+APCI): [M+H]⁺, 1bromine isotope pattern, 545/547; Anal. Calc. for C30H25BrO3S: C, 66.06,H, 4.62, N, 0.00. Found: C, 66.15, H, 4.82, N, −0.11.

[0527] Step 2

[0528](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicAcid

[0529] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid methyl ester (0.6 g, 1.10 mmol), aqueous potassium hydroxide (1.3mL of a 1 N solution, 1.3 mmol), tetrahydrofuran (15.7 mL), and enoughmethanol to create a homogeneous solution the title compound as a solid(0.58 g, 99%): NMR (DMSO-d6): δ 13.14 (br s, 1H), 8.17 (d, J=8 Hz, 1H),7.62 (ddd, J=1, 6, 8 Hz, 1H), 7.48-7.20 (m contining a doublet at δ 7.22(J=8 Hz), 9H), 7.00 (d, J=8 Hz, 2H), 5.08 (dd, J=5, 8 Hz, 1H), 3.32-3.15(two overlapping quartets, ABX pattern, 2H), 2.41 (s, 3H), 1.53 (s, 3H);MS(+APCI): [M+H]⁺, 1 bromine isotope pattern, 531/533; Anal. Calc. forC29H23BrO3S: C, 65.54, H, 4:36, N, 0.00. Found: C, 65.51, H, 4.61, N,0.09.

Example 65

[0530](2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0531] Step 1

[0532](2S)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0533] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol(10.4 g, 25.4 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(13.7 g, 76.0 mmol), triphenylphosphine (20.0 g, 76.3 mmol),diethylazodicarboxylate (12.0 mL, 76.2 mmol), and anhydrous THF (139 mL)at room temperature the title compound as a sticky foam (8.66 g, 59%):Opt. Rot. [a]25/D=−44.19° (9.188 mg/mL, MeOH); NMR(DMSO-d6): δ 8.18 (d,J=8 Hz, 1H), 7.62 (ddd, J=2,6, 8 Hz, 1H), 7.51-7.42 (m, 2H), 7.36-7.23(m, 5H), 6.98 (s, 2H), 4.78 (t, J=7 Hz, 1H), 3.56 (s, 3H), 3.29 (m, 2H),2.41 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H), 1.54 (s, 3H); MS(+APCI):[M+H], 1 bromine isotope pattern, 573/575; Anal. Calc. for C32H29BrO3S:C, 67.01, H, 5.10, N, 0.00. Found: C, 66.72, H, 4.86, N, 0.12.

[0534] Step 2

[0535] (2S)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0536] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2S)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester (4.0 g, 6.97 mmol), aqueous potassium hydroxide (8.4mL of a 1 N solution, 8.4 mmol), tetrahydrofuran (99.6 mL), and enoughmethanol to create a homogeneous solution a solid. Recrystallizationfrom 2% ethyl acetate in hexane gave the title compound as a white solid(1.45 g, 37%): mp 134-139° C.; Opt. Rot. [a]25/D=−35.86° (10.040 mg/mL,MeOH); NMR (DMSO-d6): δ 12.92 (br s, 1H), 8.17 (d, J=8 Hz, 1H), 7.63(ddd, J=2,6,8 Hz, 1H), 7.52-7.42 (m, 2H), 7.37-7.21 (m, 5H), 6.97 (s,2H), 4.72 (t, J=7 Hz, 1H), 3.25 (d, J=7 Hz, 2H), 2.41 (s, 3H), 2.25 (s,3H), 2.22 (s, 3H), 1.54 (s, 3H); MS(−ESI): [M−H]⁻, 1 bromine isotopepattern, 557/559; Anal. Calc. for C31H27BrO3S: C, 66.55, H, 4.86, N,0.00. Found: C, 66.17, H, 4.87, N, 0.01; Analytical HPLC indicates amajor component (98.1%).

Example 66

[0537](2R)-2-[4-(9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0538] From a solution of(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid (0.5 g, 0.89 mmol), glacial acetic acid (6.6 mL), and 30% aqueoushydrogen peroxide solution (1.0 mL, 9.8 mmol) there was obtained aslurry, which was immediately diluted with water and extracted withdiethyl ether. Purification by chromatography with methanol/methylenechloride gave the title compound as a pale yellow solid (0.12 g, 23%):Opt. Rot. [a]25/D=+29.57° (7.88 mg/mL, MeOH); NMR (DMSO-d6): δ 13.10 (brs, 1H), 8.28 (d, J=8 Hz, 1H), 7.74 (ddd, J=1, 7, 8 Hz, 1H), 7.63 (ddd,J=1, 7, 8 Hz, 1H), 7.39 (d, J=8 Hz, 1H), 7.36-7.18 (m, 5H), 7.01 (s,1H), 6.89 (s, 1H), 4.69 (t, J=7 Hz, 1H), 3.23 (m, 2H), 2.24, 2.21, 2.20,2.18 (4 s, mixture of sulfoxide diastereomers, 6H), 2.17 (s, 3H), 1.42(s, 3H); MS(−APCI): [M−H]⁻, 1 bromine isotope pattern, 573/575; Anal.Calc. for C31H27BrO4S: C, 64.70, H, 4.73, N, 0.00. Found: C, 64.18, H,4.44, N, −0.03. Analytical HPLC indicates two major peaks (45.16%,47.72%), a mixture of sulfoxide diastereomers.

Example 67

[0539](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid

[0540] Step 1

[0541](2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0542] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenol (0.84 g,2.33 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (3.36 g,18.6 mmol), triphenylphosphine (4.8 g, 18.3 mmol),diethylazodicarboxylate (2.92 mL, 18.5 mmol), and anhydrous benzene (75mL) at room temperature the title compound as a solid (0.50 g, 42%): NMR(DMSO-d6): δ 8.44 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.48-7.22 (m, 8H), 6.99(s, 2H), 4.69 (t, J=7 Hz, 1H), 3.55 (s, 3H), 3.27 and 3.22 (twooverlapping dd, J=6, 13 Hz, 2H), 2.70-2.40 (complex m, ABX pattern, 4H),2.38 (s, 3H), 1.53 (s, 3H), 1.10 and 1.09 (two overlapping triplets, J=8Hz, 6H); MS(+APCI): [M+H]⁺, 523.

[0543] Step 2

[0544](2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid

[0545] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.46 g, 0.88 mmol), aqueous potassium hydroxide (1.1mL of a 1 N solution, 1.1 mmol), tetrahydrofuran (12.6 mL), and enoughmethanol to create a homogeneous solution the title compound as a whitesolid (0.43 g, 89%): NMR (DMSO-d6): δ 12.91 (br s, 1H), 8.44 (s, 1H),7.94 (d, J=8 Hz, 1H), 7.47-7.22 (m, 8H), 6.98 (s, 2H), 4.61 (t, J=7 Hz,1H), 3.25 (d, J=7 Hz, 2H), 2.72 (complex m, ABX pattern, 1H), 2.66 (twooverlapping quartets, J=8 Hz, 2H), 2.55 (complex m, ABX pattern, 1H),2.38 (s, 3H), 1.55 (s, 3H), 1.10 and 1.09 (two overlapping triplets, J=8Hz, 6H); MS(−ESI): [M−H]⁻, 507; Anal. Calc. for C33H32O3S . 0.6H2O: C,76.30, H, 6.44, N, 0.00. Found: C, 76.44, H, 6.49, N, 0.04.

Example 68

[0546] {(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0547] In a manner similar to the procedure of Example 63 there wasobtained from(2R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid (0.27 g, 0.53 mmol), oxalyl chloride (0.046 mL, 0.53 mmol),N,N-dimethylformamide (two drops), benzene (9 mL), glycine ethyl esterhydrochloride (0.18 g, 1.29 mmol), and potassium carbonate (0.46; 3.33mmol) at room temperature a solid which was adsorbed onto silica gel andchromatographed with hexane:ethyl acetate (90:10). The resulting solid(0.18 g), was treated with potassium hydroxide (2.34 mL of a 1Nsolution, 2.34 mmol), tetrahydrofuran (10 mL), and enough methanol tocreate a homogeneous solution. This yielded the title compound as a paleyellow solid (0.10 g, 33%): NMR (DMSO-d6): δ 12.52 (br s, 1H), 8.48 (t,J=6 Hz, 1H), 8.43 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.48-7.16 (m, 8H), 6.93(s, 2H), 4.73 (t, J=7 Hz, 1H), 3.79 and 3.73 (two overlapping dd, J=6,17 Hz, 2H), 3.24 (dd, J=7, 14 Hz, 1H), 3.15 (dd, J=7, 14 Hz, 1H),2.80-2.50 (complex m, ABX pattern, 4H)), 2.39 (s, 3H), 1.56 (s, 3H),1.07 (t, J=8 Hz, 6H); MS(+APCI): [M+H]⁺, 566; Anal. Calc. forC35H35NO4S: C, 74.31, H, 6.24, N, 2.48. Found: C, 74.11, H, 6.69, N,2.24

Example 69

[0548] 4-(2,3-Dimethyl-naphtho[2,3 -b]furan-4-yl)-2,6-diethyl-phenol

[0549] Step 1

[0550](2-Benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3,5-diethyl-phenyl)-methanone

[0551] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3,5-diethyl-p-anisic acid (10.66 g, 51.2 mmol;prepared in three steps from 4-bromo-2,6-diethyl aniline by the methodsof J. Lipowitz and T. Cohen, J. Org. Chem. 1965, 30, 3891-3894; C. K.Bradsher. et al; J. Am. Chem. Soc. 1954, 76, 2357-2362; J. Alexander,Org. Prep. Proced. Int., 1986, 18, 2213-2215), oxalyl chloride (4.9 mL,56.2 mmol), N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran(11.4 g, 61.2 mmol), tin(IV) chloride (6.6 mL, 56.4 mmol), and anhydrousmethylene chloride (198 mL) the title compound as an oil (22 g, >100%):(DMSO-d6): δ 7.42 (s, 2H), 7.29-7.21 (m, 3H), 7.04 (d, J=7 Hz, 2H), 3.82(s, 2H), 3.74 (s, 3H), 2.61 (quartet, J=8 Hz, 4H), 2.19 (s, 3H), 1.83(s, 3H), 1.13 (t, J=8 Hz, 6H).

[0552] Step 2

[0553] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol

[0554] In a manner similar to the procedure of Example 49, Step2 therewas obtained from(2-benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3,5-diethyl-phenyl)-methanone(22 g), boron tribromide (36.8 mL, 389 mmol), and methylene chloride(180 mL) after refluxing for 4 h, the title compound as an off-whitesolid (3.09 g, 17.5%): (DMSO-d6): δ 8.29 (s, 1H), 7.96 (d, J=8 Hz, 1H),7.90 (s, 1H), 7.57 (d, J=8 Hz, 1H), 7.39 (ddd, J=1, 7, 8 Hz, 1H), 7.29(ddd, J=1, 7, 8 Hz, 1H), 6.89 (s, 1H), 2.75-2.55 (complex m, ABXpattern, 4H), 2.36 (s, 3H), 1.55 (s, 3H), 1.15 (t, J=8 Hz, 6H); MS(EI):[M+] 344; Anal. Calc. For C24H24O2: C, 83.69, H, 7.02, N, 0.00. Found:C, 82.53, H, 7.11, N, 0.05.

Example 70

[0555](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2.6-diethyl-phenoxy]-3-phenyl-propionicacid

[0556] Step 1

[0557] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2.6-diethyl-phenylester

[0558] In a manner similar to the procedure of Example 49, Step 3 therewas obtained from4-(2,3-dimethyl-naphtho[2.3-b]furan-4-yl)-2,6-diethyl-phenol (1.75 g,5.1 mmol), acetic anhydride (0.62 mL, 6.6 mmol), and pyridine (10.2 mL)a solid (2.23 g), which was used without further purification.

[0559] In a manner similar to the procedure of Example 49, Step4 therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenyl ester (2.23g 5.8 mmol), ferric chloride (247 mg, 0.29 mmol), bromine (0.34 mL, 6.4mmol), and methylene chloride (58 mL) the title compound as a solid(0.29 g, 10%): NMR (DMSO-d6): δ 8.26 (d, J=8 Hz, 1H), 7.64 (ddd, J=1, 7,8 Hz, 1H), 7.59 (d, J=9 Hz, 1H), 7.48 (ddd, J=1, 7, 8 Hz, 1 H), 7.16 (s,2H), 2.54 and 2.53 (two overlapping quartets, J=7 Hz, 4H), 2.44 (s, 3H),2.42 (s, 3H), 1.54 (s, 3H), 1.14 (t, J=7 Hz, 6H); MS(EI): [M+], 1bromine isotope pattern, 464/466.

[0560] Step 2

[0561]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol

[0562] In a manner similar to the procedure of Example 49, Step 5 therewas obtained from acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenylester (0.29 g, 0.62 mmol), aqueous potassium hydroxide (0.75 mL of a 1 Nsolution, 0.75 mmol), tetrahydrofuran (8.9 mL), and enough methanol tocreate a homogeneous solution the title compound as a solid (0.26 g,100%): NMR (DMSO-d6): δ 8.36 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.63 (d, J=8Hz, 1H), 7.59 (ddd, J=1, 7, 8 Hz, 1H), 7.41 (ddd, J=1, 7, 8 Hz, 1H),6.91 (s, 2H), 2.69 and 2.62 (two overlapping quartets, J=7 Hz, 4H), 2.41(s, 3H), 1.55 (s, 3H), 1.14 (t, J=7 Hz, 6H); MS(EI): [M+], 1 bromineisotope pattern, 422/424.

[0563] Step 3

[0564] (2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid

[0565] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol(0.26 g, 0.64 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(1.38 g, 7.66 mmol), triphenylphosphine (1.98 g, 7.55 mmol),diethylazodicarboxylate (1.2 mL, 7.62 mmol), and anhydrous benzene (0.85mL) at 100° for 36 h a solid (0.15 g, 39%), which was used withoutfurther purification.

[0566] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.15 g, 0.25 mmol), aqueous potassium hydroxide (0.98mL of a 1 N solution, 0.98 mmol), tetrahydrofuran (2.5 mL), and enoughmethanol to create a homogeneous solution the title compound as a whitesolid (0.1 g, 71%): NMR (DMSO-d6): δ 12.95 (br s, 1H), 8.23 (d, J=8 Hz;1H), 7.66 (m, 1H), 7.64-7.53 (m, 2H), 7.43-7.30 (m, 5H), 7.02 (s, 2H),4.61 (t, J 7 Hz, 1H), 3.25 (d, J=7 Hz, 2H), 2.82-2.52 (complex m, ABXpattern, 4H), 2.41 (s, 3H), 1.49 (s, 3H), 1.11 and 1.10 (two overlappingtriplets, J=7 Hz, 6H); MS(−ESI): [M−H], 1 bromine isotope pattern,569/571; Anal. Calc. for C33H31BrO4: C, 69.35, H, 5.47, N, 0.00. Found:C, 69.93, H, 5.84, N, 0.19; Analytical HPLC indicates a major component(98.3%).

Example 71

[0567](R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid

[0568] Step 1

[0569] (2R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid methyl ester

[0570] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.80g, 2.2 mmol), methyl (S)-(−)-lactate (0.24 mL, 3.3 mmol),triphenylphosphine (0.84 g, 3.2 mmol), diethylazodicarboxylate (0.51 mL,3.2 mmol), and anhydrous benzene (5 mL) at 90° the title compound as awhite solid (0.6-7 g, 68%): mp 65-66° C.; NMR (DMSO-d6): δ 8.46 (s, 1H),7.96 (d, J=8 Hz, 1H), 7.50-7.30 (m, 3H), 7.14 (m, 1H), 7.09 and 7.08(two dd, J=2, 8 Hz, atroph isomers, 1H), 6.95 and 6.92 (two d, J=8 Hz,atroph isomers, 1H), 5.14 and 5.11 (two quartets, J=7 Hz, atrophisomers, 1H), 3.75 and 3.70 (two s, atroph isomers, 3H), 3.43 (m, 1H),2.41 (s, 3H), 2.00 (m, 2H), 1.77-1.50 (m containing a doublet (J=7 Hz)at δ 1.61 and a singlet at δ 1.57, 12H); MS(EI): [M+], 458; Anal. Calc.for C29H30O3S: C, 75.95, H, 6.59, N, 0.00. Found: C, 74.93, H, 6.55, N,−0.09.

[0571] Step 2

[0572](2R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid

[0573] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid methyl ester (0.60 g, 1.3 mmol), aqueous potassium hydroxide (1.98mL of a 1 N solution, 1.98 mmol), tetrahydrofuran (9 mL), and methanol(3 mL) the title compound as a white solid (0.55 g, 95%): Opt. Rot.[a]25/D=+7.95° (10.068 mg/mL, MeOH); NMR (DMSO-d6): δ 13.02 (br s, 1H),8.46 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.50-7.30 (m, 3H), 7.13 and 7.12(two doublets, J=2 Hz, atroph isomers, 1H), 7.11 and 7.09 (two dd, J=2,8 Hz, atroph isomers, 1H), 6.93 and 6.91 (two doublets, J=8 Hz, atrophisomers, 1H), 4.95 (q, J=7 Hz, 1H), 3.44 (m, 1H), 2.41 (s, 3H), 2.00 (m,2H), 1.79-1.50 (m containing a doublet (J=7 Hz) at δ 1.60 and a singletat δ 1.58, 12H); MS(EI): [M+], 444; Anal. Calc. for C28H28O3S: C, 75.64,H, 6.35, N, 0.00. Found: C, 74.10, H, 6.32, N, −0.09; Analytical HPLCindicates a major component (99.99%).

Example 72

[0574](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid

[0575] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.37 g, 0.99 mmol), methyl (S)-(−)-lactate (0.75 mL, 7.9 mmol),triphenylphosphine (2.1 g, 8.0 mmol), diethylazodicarboxylate (1.23 mL,7.8 mmol), and anhydrous benzene (1.0 mL) at 90° for 18 h the titlecompound as a solid (0.20 g, 28%), which was used without furtherpurification.

[0576] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid methyl ester (0.20 g, 0.37 mmol), aqueous potassium hydroxide (0.74mL of a 1 N solution, 0.74 mmol), tetrahydrofuran (3.7 mL), and enoughmethanol to create a homogeneous solution the title compound as anoff-white solid (0.18 g, 95%): NMR (DMSO-d6): δ 13.00 (br s, 1H), 8.18(d, J=8 Hz, 1H), 7.63 (m, 1H), 7.50-7.40 (m, 2H), 7.14 and 7.13 (twodoublets, J=2 Hz, atroph isomers, 1H), 7.10 and 7.09 (two dd, J=2,8 Hz,atroph isomers, 1H), 6.93 and 6.91 (two doublets, J=8 Hz, atrophisomers, 1H), 4.94 (q, J=7 Hz, 1H), 3.41 (m, 1H), 2.42 (s, 3H), 1.98 (m,2H), 1.78-1.46 (m containing two doublets at δ 1.59 and 1.58 (J=7 Hz,atroph isomers) and a singlet at δ 1.54, 12H); MS(−ESI): [M−H], 1bromine isotope pattern, 521/523; Anal. Calc. for C28H27BrO3S: C, 64.24,H, 5.20, N, 0.00. Found: C, 64.11, H, 5.52, N, 0.10.

Example 73

[0577]4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl-2-cyclopentyl-phenoxy]-butyricacid

[0578] Step 1

[0579]4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid methyl ester

[0580] A solution of2-cyclopentyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol(0.30 g, 0.81 mmol), 4-bromobutyric acid, methyl ester (1.5 mL, 13.0mmol), 60% sodium hydride (0.09 g, 2.3 mmol), potassium carbonate (1.0g, 7.2 mmol), and anhydrous benzene (2 mL) was heated at 100° for 36 h.Purification by chromatography with hexanes/ethyl acetate gave the titlecompound as a solid (0.23 g, 52%): NMR (DMSO-d6): δ 8.18 (d, J=8 Hz,1H), 7.62 (ddd, J=2,6,8 Hz, 1H), 7.50-7.41 (m, 2H), 7.16-7.04 (m, 3H),4.11 (m, 2H), 3.63 (s, 3H), 3.31 (quintet, J=8 Hz, 1H), 2.57 (t, J=7 Hz,2H), 2.42 (s, 3H), 2.07 (quintet, J=7 Hz, 2H), 1.95 (m, 2H), 1.74-1.45(m containing a singlet at δ 1.56, 9H); MS(EI): [M+], 1 bromine isotopepattern, 550/552.

[0581] Step 2

[0582]4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid

[0583] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from4-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid methyl ester (0.23 g, 0.42 mmol), aqueous potassium hydroxide (1.66mL of a 1 N solution, 1.66 mmol), tetrahydrofuran (9.2 mL), and enoughmethanol to create a homogeneous solution the title compound as anoff-white solid (0.22 g, 100%): NMR (DMSO-d6): δ 12.15 (br s, 1H), 8.18(d, J=8 Hz, 1H), 7.62 (ddd, J=2,6,8 Hz, 1H), 7.51-7.41 (m, 2H),7.14-7.05 (m, 3H), 4.10 (m, 2H), 3.37 (m, 1H), 2.48 (t, J=7 Hz, 1H),2.41 (s, 3H), 2.04 (quintet, J=7 Hz, 2H), 1.96 (m, 2H), 1.72-1.44 (mcontaining a singlet at δ 1.56, 9H); MS(−ESI): [M−H]⁻, 1 bromine isotopepattern, 535/537; Anal. Calc. for C29H29BrO3S: C, 64.80, H, 5.44, N,0.00. Found: C, 64.20, H, 5.50, N, 0.03.

Example 74

[0584] 2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenol

[0585] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3-cyclopentyl-p-anisic acid (10 g, 45.4 mmol,RN-59216-82-9); oxalyl chloride (4.4 mL, 50.4 mmol),N,N-dimethylformamide (2 drops), 2,3-dimethyl-5-benzylfuran (10.1 g,54.2 mmol), tin(IV) chloride (5.8 mL, 49.6 mmol), and anhydrousmethylene chloride (183 mL) an oil (18.8 g), which was used withoutfurther purification

[0586] In a manner similar to the procedure of Example 49, Step2 therewas obtained from(2-benzyl-4,5-dimethyl-furan-3-yl)-(3-cyclopentyl-4-methoxy-phenyl)-methanone(18.8 g, 48.4 mmol), boron tribromide (34.8 mL, 368 mmol), and methylenechloride (167 mL) at 50-55° for 2 h the title compound as a light tansolid (1.56 g, 9.6%): (DMSO-d6): δ 9.46 (s, 1H), 7.96 (d, J=8 Hz, 1H),7.90 (s, 1H), 7.54 (d, J=8 Hz, 1H), 7.39 (ddd, J=1, 7, 8 Hz, 1H), 7.29(ddd, J=1, 7, 8 Hz, 1H), 7.04 (d, J=2 Hz, 1H), 6.97 (dd, J=2, 8 Hz, 2H),6.91 (d, J=8 Hz, 1H), 3.38-3.26 (m, 1H), 2.36 (s, 3H), 1.96 (m, 2H),1.74-1.44 (m containing a singlet at δ 1.55, 9H); MS(EI): [M+] 356;Anal. Calc. for C25H24O2: C, 84.24, H, 6.79, N, 0.00. Found: C, 83.48,H, 6.71, N, 0.04

Example 75

[0587] Acetic acid2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenyl ester

[0588] In a manner similar to the procedure of Example 49, Step 3 therewas obtained from2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenol (4.81 g,13.5 mmol), acetic anhydride (1.60 mL, 17.0 mmol), pyridine (27 mL), andmethylene chloride (27 mL) a residue, which was chromatographed withhexane/ethyl acetate to give the title compound as a solid (0.92 g,17%): NMR (DMSO-d6): δ 8.00 (d, J=8 Hz, 1H), 7.97 (s, 1H), 7.42 (ddd,J=1, 7, 8 Hz, 1H), 7.34 (ddd, J=1, 7, 8 Hz, 1H), 7.30 (d, J=2 Hz, 1H),7.22 (dd, J=2, 8 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 3.14 (m, 1H), 2.37 (s,3H), 2.36 (s, 3H), 1.96 (m, 2H), 1.74-1.44 (m containing a singlet at δ1.52, 9H); MS(+ESI): [M+H]⁺ 399; Anal. Calc. for C27H26O3: C, 81.38, H,6.58, N, 0.00. Found: C, 80.76, H, 6.65, N, 0.05. 5.24, N, 0.03.

Example 76

[0589](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid

[0590] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from2-ethyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.47 g,4.42 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (4.78 g,26.5 mmol), triphenylphosphine (6.96 g, 26.5 mmol),diethylazodicarboxylate (4.18 mL, 26.5 mmol), and anhydrous benzene (8.8mL) a solid (0.16 g), which was used without further purification.

[0591] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(R)-2-[4-(2-,3dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.16 g, 0.32 mmol), aqueous potassium hydroxide (0.65mL of a 1 N solution, 0.65 mmol), tetrahydrofuran (3.2 mL), and enoughmethanol to create a homogeneous solution the title compound as a yellowfoam (0.10 g, 63%): NMR (DMSO-d6): δ 13.11 (br s, 1H), 8.43 (d, J=2 Hz,1H), 7.93 (dd, J=3, 8 Hz, 1H), 7.48-7.20 (m, 8H), 7.10-7.00 (m, 2H),6.86 (dd, J=4, 9 Hz, 1H), 5.08 and 5.04 (two dd, J=4, 8 Hz, atrophisomers, 1H), 3.42 (m, ABX pattern, 2H), 2.75-2.52 (complex m, ABXpattern, atroph isomers, 2H), 2.38 (s, 3H), 1.56 and 1.54 (two s, atrophisomers, 3H), 1.08 and 1.06 (two t, J=7 Hz, 3H); MS(EI): [M+], 480;Anal. Calc. for C31H28O3S: C, 77.47, H, 5.87, N, 0.00. Found: C, 74.55,H, 5.87, N, 0.20.

Example 77

[0592](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid

[0593] Step 1

[0594] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenyl ester

[0595] In a manner similar to the procedure of Example 49, Step 3 therewas obtained from2-ethyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (1.4 g, 4.2mmol), acetic anhydride (0.52 mL, 5.5 mmol), and pyridine (8.4 mL) aresidue, which was chromatographed with hexane/ethyl acetate to give thetitle compound as a solid (1.62 g, >100%): NMR (DMSO-d6): δ 8.49 (s,1H), 7.97 (d, J=9 Hz, 1H), 7.50-7.43 (m, 1H), 7.40-7.35 (m, 2H), 7.27(s, 1H), 7.21 (s, 2H), 2.57 (two overlapping quartets, J=8 Hz, 2H), 2.40(s, 3H), 2.37 (s, 3H), 1.58 (s, 3H), 1.13 (t, J=8Hz, 3H); MS(EI): [M+]374; Anal. Calc. for C24H22O2S: C, 76.97, H, 5.92, N, 0.00. Found: C,75.72, H, 5.92, N, 0.03.

[0596] Step 2

[0597] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenylester

[0598] In a manner similar to the procedure of Example 49, Step4 therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenyl ester (1.53g, 4.1 mmol), ferric chloride (41 mg, 0.22 mmol), bromine (0.23 mL, 4.5mmol), and methylene chloride (35 mL) the title compound as a solid(0.48 g, 26%): NMR (DMSO-d6): δ 8.21 (d, J=9 Hz, 1H), 7.65 (ddd, J=2, 6,8 Hz, 1H), 7.57-7.40 (m, 2H), 7.30 (s, 1H), 7.23 (s, 2H), 2.56 (twooverlapping quartets, J=8 Hz, 2H), 2.43 (s, 3H), 2.37 (s, 3H), 1.56 (s,3H), 1.13 (t, J=8 Hz, 3H).

[0599] Step 3

[0600]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenol

[0601] In a manner similar to the procedure of Example 49, Step 5 therewas obtained from acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenylester (1.5 g, 3.3 mmol), aqueous potassium hydroxide (4.0 mL of a 1 Nsolution, 4.0 mmol), tetrahydrofuran (55 mL), and methanol (37 mL) thetitle compound as a green foam (1.4 g, >100%): NMR (DMSO-d6): δ 9.55 (s,1H), 8.16 (d, J=9 Hz, 1H), 7.62 (ddd, J=1, 7, 8 Hz, 1H), 7.54 (d, J=8Hz, 1H), 7.44 (ddd, J=1, 7, 8 Hz, 1H), 7.05-6.87 (m, 3H), 2.60 (complexm, ABX pattern, 2H), 2.41 (s, 3H), 1.59 (s, 3H), 1.13 (t, J=8 Hz, 3H).

[0602] Step 4

[0603](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0604] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenol(0.45 g, 1.16 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.31 g, 1.72 mmol), triphenylphosphine (0.45 g, 1.72 mmol),diethylazodicarboxylate (0.27 mL, 1.71 mmol), and anhydrous benzene (5mL) at 90° for 18 h the title compound as a glassy residue (0.22 g,33%): NMR (DMSO-d6): δ 8.22 (d, J=9 Hz, 1H), 7.66 (ddd, J=3, 6, 8 Hz,1H), 7.59-7.22 (m, 7H), 7.20-7.02 (m, 2H), 6.92 (dd, J=2, 8 Hz, 1H),5.31 (m, 1H), 3.74 and 3.70 (two s, atroph isomers, 3H), 3.32 (m, 2H),2.64 (complex m, 2H), 2.45(s, 3H), 1.55 (s, 3H), 1.12 and 1.10 (two t,J=7 Hz, atroph isomers, 3H).

[0605] Step 5

[0606](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid

[0607] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.22 g, 0.38 mmol), aqueous potassium hydroxide (0.46mL of a 1 N solution, 0.46 mmol), tetrahydrofuran (15 mL), and methanol(5 mL) the title compound as a white solid (0.19 g, 90%): Opt. Rot.[a]25/D=+1.55° (8.396 mg/mL, MeOH); NMR (DMSO-d6): δ 13.15 (br s, 1H),8.17 (dd, J=4, 9 Hz, 1H), 7.66-7.58 (m, 1H), 7.50-7.21 (m, 7H),7.11-7.04 (m, 2H), 6.88 (dd, J=4, 9 Hz, 1H), 5.09 and 5.06 (two dd, J=4,8 Hz, atroph isomers, 1H), 3.24 (complex m, ABX pattern, 2H), 2.66 and2.56 (two overlapping doublet of quartets, ABX pattern, atroph isomers,2H), 2.42 and 2.40 (two s, atroph isomers, 3H), 1.53 and 1.52 (two s,atroph isomers, 3H), 1.08 and 1.06 (two t, J=8 Hz, atroph isomers, 3H);MS(EI): [M+], 1 bromine isotope pattern, 558/560; Anal. Calc. forC31H27BrO3S: C, 66.54, H, 4.86, N, 0.00. Found: C, 66.91, H, 5.28, N,−0.07.

Example 78

[0608] 2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol

[0609] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3-bromo-5-ethyl-p-anisic acid (4.95 g, 19.1 mmol),oxalyl chloride (1.8 mL, 20.6 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylfuran (4.3 g, 23.1 mmol), tin(IV) chloride (2.5 mL,21.4 mmol), and anhydrous methylene chloride (72 mL) an oil (7.85 g),which was used without further purification.

[0610] In a manner similar to the procedure of Example 49, Step 2 therewas obtained from (2-benzyl-4,5-dimethyl-furan-3-yl)-(3-bromo-5-ethyl-4-methoxy-phenyl)-methanone (7.85 g, 18.4 mmol), borontribromide (13.2 mL, 14.0 mmol), and methylene chloride (63 mL) at 50°for 2 h the title compound as a white solid (0.85 g, 12%): (DMSO-d6): δ9.17 (s, 1H), 7.99 (d, J=8 Hz, 1H), 7.95 (s, 1H), 7.52 (d, J=8Hz, 1H),7.42 (ddd, J=1, 7, 8 Hz, 1H), 7.37-7.30 (m, 2H), 7.10 (d, J=2 Hz, 1H),2.80-2.60 (complex m, ABX pattern, 2H), 2.37 (s, 3H), 1.59 (s, 3H), 1.15(t, J=8 Hz, 3H); MS(EI): [M+], 1 bromine isotope pattern, 394/396; Anal.Calc. for C22H19BrO2: C, 66.85, H, 4.84, N, 0.00. Found: C, 67.07, H,4.85, N, 0.05.

Example 79

[0611] (R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionic acid

[0612] Step 1

[0613](2R)-2-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0614] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.30g, 0.76 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester- (0.54g, 3.0 mmol), triphenylphosphine (0.80 g, 3.1 mmol),diethylazodicarboxylate (0.48 mL, 3.0 mmol), and anhydrous benzene (1.0mL) at 100° for 12 h the title compound as a solid (0.37 g, 88%): NMR(DMSO-d6): δ 8.02 (d, J=8 Hz, 1H), 7.99 (s, 1H), 7.54-7.22 (m, 10H),5.08 and 5.02 (two dd, J=6, 8 Hz, atroph isomers, 3H), 3.60 and 3.57(two s, atroph isomers, 3H), 3.47-3.30 (m, 2H), 2.80-2.52 (complex m,ABX pattern, atroph isomers, 2H), 2.40 and 2.39 (two s, atroph isomers,3H), 1.58 and 1.53 (two s, atroph isomers, 3H), 1.12 and 1.10 (two t,J=8 Hz, atroph isomers, 3H); MS(EI): [M+], 1 bromine isotope pattern,556/558.

[0615] Step 2

[0616](2R)-2-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid

[0617] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.34 g, 0.61 mmol), aqueous potassium hydroxide (1.2mL of a 1 N solution, 1.2 mmol), tetrahydrofuran (6.0 mL), and enoughmethanol to create a homogeneous solution the title compound as a whitefoam (0.31 g, 94%): NMR (DMSO-d6): δ 8.01 (d, J=8 Hz, 1H), 7.97 (d, J=2Hz, 1H), 7.48 (d, J=9 Hz, 2H), 7.46-7.22 (m, 9H), 7.20 (dd, J=2, 6 Hz,1H), 5.03 (m, 1H), 3.35 (m, 2H), 2.94-2.55 (complex m, ABX pattern, 2H),2.38 and 2.36 (two s, atroph isomers, 3H), 1.56 and 1.51 (two s, atrophisomers, 3H), 1.11 and 1.10 (two t, J=7 Hz, atroph isomers, 3H); MS(EI):[M+], 1 bromine isotope pattern, 542/544; Anal. Calc. for C31H27BrO4: C,68.51, H, 5.01, N, 0.00. Found: C, 68.22, H, 5.42, N, 0.10.

Example 80

[0618]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid

[0619] Step 1

[0620]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid methyl ester

[0621] A solution of2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.30g, 0.76 mmol), 60% sodium hydride (33 mg, 0.83 mmol), 4-bromobutyricacid, methyl ester (0.44 mL, 3.82 mmol), and anhydrous benzene (1.0 mL)was heated at 100° for 6 h. A second portion of 4-bromobutyric acidmethyl ester (0.45 mL, 3.91 mmol) and potassium carbonate (0.5 g, 3.62mmol) was added and the reaction mixture was heated at 100° for 6 h. Thecrude reaction mixture was chromatographed with hexane/ethyl acetate togive the title compound as a solid (0.31 g, 82%): NMR (DMSO-d6): δ 8.00(d, J=8 Hz, 1H), 7.98 (s, 1H), 7.48 (d,-J=8 Hz, 1H), 7.46 (d, J=2 Hz,1H), 7.43 (ddd, J=1, 7, 8 Hz, 1H), 7.35 (ddd, J=1, 7, 8 Hz, 1H), 7.26(d, J=2 Hz, 1H), 4.03 (dd, J=6, 9 Hz, 1H), 3.98 (dd, J=6, 9 Hz, 1H),3.63 (s, 3H), 2.74 (d of quartets, J=7, 15 Hz, 1H), 2.69 (d of quartets,J=7, 15 Hz, 1H), 2.62 (t, J=7 Hz, 2H), 2.38 (s, 3H), 2.09 (quintet, J=7Hz, 2H), 1.56 (s, 3H), 1.18 (t, J=7 Hz, 3H); MS(EI): [M+], 1 bromineisotope pattern, 494/496.

[0622] Step 2

[0623]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid

[0624] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from4-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid methyl ester (0.31 g, 0.63 mmol), aqueous potassium hydroxide (1.25mL of a 1 N solution, 1.25 mmol), tetrahydrofuran (6.3 mL), and enoughmethanol to create a homogeneous solution the title compound as a whitefoam (0.26 g, 87%): NMR (DMSO-d6): δ 12.15 (br s, 1H), 8.01 (d, J=8 Hz,1H), 7.98 (s, 1H), 7.48 (d, J=8 Hz, 1H), 7.46 (d, J=2 Hz, 1H), 7.42(ddd, J=1, 7, 8 Hz, 1H), 7.35 (ddd, J=1, 7, 8 Hz, 1H), 7.26 (d, J=2 Hz,1H), 4.04 (dd, J=6, 9 Hz, 1H), 3.98 (dd, J=6, 9 Hz, 1H), 2.74 (d ofquartets, J=7, 15 Hz, 1H), 2.71 (d of quartets, J=7, 15 Hz, 1H), 2.53(t, J=7 Hz, 2H), 2.38 (s, 3H), 2.06 (quintet, J=7 Hz, 2H), 1.56 (s, 3H),1.19 (t, J=7 Hz, 3H); MS(−ESI): [M−H]⁻, 1 bromine isotope pattern,479/481; Anal. Calc. for C26H25BrO4: C, 64.87, H, 5.23, N, 0.00. Found:C, 64.94, H, 5.34, N, 0.08.

Example 81

[0625]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyramide0.4 hydrate

[0626] A solution of4-[2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid (60 mg, 0.12 mmol), oxalyl chloride (10.8 μL, 0.12 mmol),N,N-dimethylformamide (2.0 μL), and methylene chloride (1.0 mL) wasstirred at room temperature. After 2.5 h a saturated solution of ammoniain acetonitrile (5 mL) was added and the resulting mixture was stirredat room temperature for 2 days. Concentration under reduced pressuregave a residue, which was suspended in 3% ethanol in water (31 mL) andstirred at room temperature for 18 h. The slurry was filtered, washedwell with water, and air dried to give the title compound as anoff-white solid (52.6 mg, 88%): NMR (DMSO-d6): δ 8.00 (d,-J=8 Hz, 1H),7.98 (s, 1H), 7.49 (d, J=8 Hz, 1H), 7.45 (d, J=2 Hz, 1H), 7.43 (ddd,J=1, 7, 8 Hz, 1H), 7.35 (ddd overlapping with a br s, J=1, 7, 8 Hz, 2H),7.25 (d, J=2 Hz, 1H), 6.79 (br s, 1H), 4.01 (dd, J=6, 9 Hz, 1H), 3.96(dd, J=6, 9 Hz, 1H), 2.75 (d of quartets, J=7, 15 Hz, 1H), 2.71 (d ofquartets, J=7, 15 Hz, 1H), 2.38 (s, 3H), 2.35 (t, J=7 Hz, 2H), 2.04(quintet, J=7 Hz, 2H), 1.56 (s, 3H), 1.19 (t, J=7 Hz, 3H); MS(+ESI):[M+H]⁺, 1 bromine isotope pattern, 480/482; Anal. Calc. forC26H26BrNO3Y0.4H2O: C, 64.04, H, 5.54, N, 2.87. Found: C, 64.01, H,5.43, N, 2.89.

Example 82

[0627] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol

[0628] Step 1

[0629] (2-Benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3-ethyl-phenyl)-methanone

[0630] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3-ethyl-p-anisic acid (5.0 g, 27.7 mmol), oxalylchloride (2.7 mL, 31.0 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylfuran (6.2 g, 33.3 mmol), tin(IV) chloride (3.6 mL,30.8 mmol), and anhydrous methylene chloride (177 mL) the title compoundas an oil (7.24 g, 75%): (DMSO-d6): δ 7.61 (dd, J=2, 8 Hz, 1H), 7.54 (d,J=2 Hz, 1H), 7.28-7.13 (m, 3H), 7.09-7.03 (m, 3H), 3.86 (s, 3H), 3.82(s, 2H), 2.55 (q, J=7 Hz, 2H), 2.16 (s, 3H), 1.78 (s, 3Hy, 1.08 (t, J=7Hz, 3H).

[0631] Step 2

[0632] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol

[0633] In a manner similar to the procedure of Example 49, Step 2 therewas obtained from(2-benzyl-4,5-dimethyl-furan-3-yl)-(4-methoxy-3-ethyl-phenyl)-methanone(7.0 g, 20.1 mmol), boron tribromide (14.4 mL, 152.3 mmol), andmethylene chloride (69 mL) the title compound as an off-white solid(0.61 g, 9.6%): (DMSO-d6): δ 9.45 (s, 1H), 7.97 (d, J=8 Hz, 1I), 7.90(s, 1H), 7.55 (d, J=8 Hz, 1H), 7.39 (ddd, J=1, 7, 8 Hz, 1H), 7.29 (ddd,J=1, 7, 8 Hz, 1H), 7.02 (d, J=2 Hz, 1H), 6.98 (dd, J=2, 8 Hz, 1H), 6.91(d, J=8 Hz, 1H), 2.63 (d of quartets, J=7, 14 Hz, 1H), 2.58 (d ofquartets, J=7, 14 Hz, 1H), 2.36 (s, 3H), 1.56 (s, 3H), 1.14 (t, J=7 Hz,3H); MS(EI): [M+] 316.

Example 83

[0634](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid

[0635] Step 1

[0636](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3-propyl-phenyl)-methanone

[0637] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3-propyl-p-anisic acid (3.0 g, 15.4 mmol), oxalylchloride (1.48 mL, 17.0 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylthiophene (3.75 g, 18.5 mmol), tin(IV) chloride(1.99 mL, 17.0 mmol), and anhydrous methylene chloride (99 mL) the titlecompound as an oil (2.11 g, 38%): (DMSO-d6): δ 7.58 (dd, J=2, 8 Hz, 1H),7.53 (d, J=2 Hz, 1H), 7.25-7.11 (m, 3H), 7.10-7.03 (m, 3H), 3.86 (s,3H), 3.84 (s, 2H), 2.54 (t, J=7 Hz, 2H), 2.26 (s, 3H), 1.81 (s, 3H),1.51 (sextet, J=7 Hz, 2H), 0.87 (t, J=7 Hz, 3H); MS(EI): [M+] 378.

[0638] Step 2

[0639] 4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol

[0640] In a manner similar to the procedure of Example 49, Step2 therewas obtained from(2-benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-3-propyl-phenyl)-methanone(2.70 g, 7.1 mmol), boron tribromide (5.12 mL, 54.2 mmol), and methylenechloride (24.5 mL) the title compound as a solid (1.77 g, 71%):(DMSO-d6): δ 9.44 (s, 1H), 8.42 (s, 1H), 7.93 (d, J=8 Hz, 1H), 7.50-7.25(m, 3H), 7.05-6.88 (m, 3H), 2.61 (m, 1H), 2.52 (m, 1H), 2.39 (s, 3H),1.70-1.50 (m containing a singlet at δ 1.63, 5H), 0.88 (t, J=7 Hz, 3H);MS(EI): [M+] 346.

[0641] Step 3

[0642] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenyl ester

[0643] In a manner similar to the procedure of Example 49, Step 3 therewas obtained from4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol (1.3 g, 3.8mmol), acetic anhydride (0.46 mL, 4.9 mmol), and pyridine (7.5 mL) aresidue, which was chromatographed with hexane/ethyl acetate to give thetitle compound as a solid (0.81 g, 56%): NMR (DMSO-d6): δ 8.50 (s, 1H),7.98 (d, J=9 Hz, 1H), 7.51-7.44 (m, 1H), 7.40-7.36 (m, 2H), 7.26 (s,1H), 7.23 (s, 2H), 2.55 (m, 2H), 2.42 (s, 3H), 2.38 (s, 3H), 1.64-1.53(m containing a singlet δ 1.61, 5H), 0.88 (t, J=7 Hz, 3H); MS(EI): [M+]388.

[0644] Step 4

[0645] Acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenylester

[0646] In a manner similar to the procedure of Example 49, Step4 therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenyl ester (0.80g, 2.1 mmol), ferric chloride (16.7 mg, 0.10 mmol), bromine (0.12 mL,2.3 mmol), and methylene chloride (21 mL) the title compound as a solid(0.38 g, 39%): NMR (DMSO-d6): δ 8.20 (d, J=9 Hz, 1H), 7.65 (ddd, J=1, 6,8 Hz, 1H), 7.48 (ddd, J=1, 6, 8 Hz, 1H), 7.43 (d, J=8 Hz, 1H), 7.28 (s,1H), 7.23 (s, 2H), 2.53 (m, 2H), 2.43 (s, 3H), 2.36 (s, 3H), 1.63-1.50(m containing a singlet at δ 1.57, 5H), 0.86 (t, J=7 Hz, 3H); MS(EI):[M+], 1 bromine isotope pattern, 466/468.

[0647] Step 5

[0648](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid

[0649] In a manner similar to the procedure of Example 49, Step 5 therewas obtained from acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenylester (0.36 g, 0.77 mmol), aqueous potassium hydroxide (0.92 mL of a 1 Nsolution, 0.92 mmol), tetrahydrofuran (11.4 mL), and methanol (7.6 mL) asolid,4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol(0.62 g), which was used without further purification.

[0650] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenol(0.77 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (1.12 g,6.2 mmol), triphenylphosphine (1.60 g, 6.1 mmol),diethylazodicarboxylate (0.96 mL, 6.1 mmol), and anhydrous benzene (2.5mL) at 85° for 3 days a solid,(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.23 g), which was used without further purification.

[0651] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.23 g, 0.39 mmol), aqueous potassium hydroxide (0.93mL of a 1 N solution, 0.93 mmol), tetrahydrofuran (4.6 mL), and enoughmethanol to create a homogeneous solution the title compound as a yellowfoam (0.17 g, 74%): NMR (DMSO-d6): δ 13.15 (br s, 1H), 8.18 (d, J=3, 9Hz, 1H), 7.67-7.59 (m, 1H), 7.50-7.23 (m, 7H), 7.52-7.40 (m, 2H), 6.88(dd, J=5, 8 Hz, 1H), 5.15-5.02 (m, 1H), 3.24 (m, 2H), 2.73-2.53 (m, 2H),2.42 (s, 3H), 1.60-1.40 (m containing two singlets at δ 1.56 and 1.54,atroph isomers, 5H), 0.87 and 0.85 (two t, J=7 Hz, atroph isomers, 3H);MS(EI): [M+], 1 bromine isotope pattern, 572/574.

Example 84

[0652][9-Bromo-4-(4-methoxy-3,5-dimethylphenyl)-3-methylnaphtho[2,3-b]thien-2-yl]methylacetate

[0653] A solution of4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-anisole(2.0 g, 4.7 mmol), sulfuryl chloride (0.42 mL, 5.3 mmol),diisopropylethylamine (0.90 mL, 5.2 mmol), and anhydrous methylenechloride (24 mL) was stirred at 0° C. for approximately 2 h. The crudereaction mixture was then diluted with diethyl ether, washed twice withwater, once with brine, and then dried (Na2SO4). Concentration underreduced pressure gave a residue, which was immediately treated withsodium acetate (1.2 g, 14.6 mmol) and N,N-dimethylformamide (16.8 mL).After 24 h the reaction mixture was diluted with diethyl ether, washedthree times with water, once with brine, and then dried (Na2SO4).Concentration under reduced pressure gave a residue, which waschromatographed with hexane/ethyl acetate to give the title compound asa yellow foam (0.36 g, 27%): (DMSO-d6): δ 8.41 (s, 1H), 8.21 (d, J=9 Hz,1H), 7.68 (ddd, J=2, 6, 8 Hz, 1H), 7.57-7.45 (m, 2H), 7.05 (s, 2H), 3.78(s, 3H), 2.30 (s, 6H), 2.08 (s, 3H), 1.68 (s, 3H); MS(EI): [M+], 1bromine isotope pattern, 482/484; Anal. Calc. for C25H23BrO3S: C, 62.11,H, 4.80, N, 0.00. Found: C, 61.86, H, 4.75, N, 0.04.

Example 85

[0654]4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenylacetate

[0655] Step 1

[0656] Acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methyl-phenyl ester

[0657] In a manner similar to the procedure of Example 49, Step 1 therewas obtained from 3-methyl-p-anisic acid (10 g, 60.2 mmol), oxalylchloride (5.77 mL, 66.1 mmol), N,N-dimethylformamide (2 drops),2,3-dimethyl-5-benzylthiophene (14.6 g, 72.2 mmol), tin(IV) chloride(7.75 mL, 66.2 mmol), and anhydrous methylene chloride (300 mL) an oil(24.4 g), which was used without further purification.

[0658] In a manner similar to the procedure of Example 49, Step2 therewas obtained from(2-benzyl-4,5-dmethyl-thiophen-3-yl)-(4-methoxy-3-methyl-phenyl)-methanone(24.4 g), boron tribromide (17.1 mL, 180.9 mmol), and methylene chloride(120 mL) a residue. This residue was treated with acetic anhydride (7.4mL, 78.4 mmol), pyridine (58 mL), and methylene chloride (400 mL) in amanner similar to the procedure of Example 49, Step 3. The usual work upgave the title compound as a solid (9.83 g, 45.5%): NMR (DMSO-d6): δ8.48 (s, 1H), 7.97 (d, J=8 Hz, 1H), 7.50-7.33 (m, 3H), 7.27 (s, 1H),7.21 (s, 2H), 2.40 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 1.58 (s, 3H);MS(+APCI): [M+H] 361.

[0659] Step 2

[0660]4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenylacetate

[0661] In a manner similar to the procedure of Example 49, Step4 therewas obtained from acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methyl-phenyl ester (5.0g, 13.9 mmol), ferric chloride (0.11 g, 0.68 mmol), bromine (14.3 mL ofa 1.07 M solution in carbon tetrachloride, 15.3 mmol), and methylenechloride (63 mL) the title compound as a solid (5.44 g, 90.7%): NMR(DMSO-d6): δ 8.20 (d, J=9 Hz, 1H), 7.65 (ddd, J=2, 6, 8 Hz, 1H),7.52-7.42 (m, 2H), 7.30 (s, 1H), 7.23 (s, 2H), 2.43 (s, 3H), 2.36 (s,3H), 2.20 (s, 3H). 1.56 (s, 3H); MS(EI): [M+], 1 bromine isotopepattern, 438/440; Anal. Calc. for C23H19BrO2S: C, 62.87, H, 4.36, N,0.00. Found: C, 62.27, H, 3.99, N, 0.10.

Example 86

[0662] Acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester

[0663] Step 1

[0664] Acetic acid4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester

[0665] In a manner similar to the procedure of Example 49, Step4 therewas obtained from acetic acid4-(2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester (10.0 g, 26.7 mmol), ferric chloride (0.23 g, 1.42 mmol), bromine(1.51 mL in methylene chloride (38 mL), 29.4 mmol), and methylenechloride (231 mL) acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester (6.68 g, 55%) and the title compound as a yellow solid (1.60 g):NMR (DMSO-d6): δ 8.28 (m, 1H), 7.62-7.56 (m, 2H), 7.41-7.37 (m, 1H),7.06 (s, 2H), 4.70 (s, 2H), 2.42 (s, 3H), 2.24 (s, 6H), 1.72 (s, 3H);MS(EI): [M+], 2 bromine isotope pattern, 530/532/534; Anal. Calc. forC24H20Br2O2S: C, 54.15, H, 3.79, N, 0.00. Found: C, 53.81, H, 3.61, N,0.10.

[0666] Step 2

[0667] Acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester

[0668] Acetic acid4-(9-bromo-2-bromomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester (1.21 g, 2.27 mmol) was treated with diethylamine (0.71 mL, 6.82mmol), potassium carbonate (0.94 g, 6.82 mmol), andN,N-dimethylformamide (12.1 mL). After 1 h at room temperature thereaction mixture was poured in water (250 mL), filtered, and rinsed wellwith water. Air drying gave the title compound as a yellow solid (1.13g, 94.5%): NMR (DMSO-d6): δ 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47 (d, 2H), 7.13 (s, 2H), 3.73 (s, 2H), 2.58-2.52 (q, 4H), 2.40 (s, 3H), 2.16(s, 6H), 1.61 (s, 3H), 1.02 (t, 6H); MS(EI): [M+], 1 bromine isotopepattern, 523/525; Anal. Calc. for C28H30BrNO2S: C, 64.12, H, 5.77, N,2.67. Found: C, 63.30, H, 5.67, N, 2.55.

Example 87

[0669]2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0670] Step 1

[0671]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol

[0672] In a manner similar to the procedure of Example 49, Step 5 therewas obtained from acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester (1.13 g, 2.15 mmol), aqueous potassium hydroxide (2.58 mL of a 1 Nsolution, 2.58 mmol), tetrahydrofuran (28 mL), and methanol (19 mL) thetitle compound as a yellow solid (1.0 g, 961%): NMR (DMSO-d6): δ 8.47(s, 1H), 8.17 (d, 1H), 7.64-7.59 (m, 1H), 7.55-7.45 (m, 1H), 7.45-7.39(m, 1H), 6.90 (s, 2H), 3.72 (s, 2H), 2.60-2.50 (m, 4H), 2.23 (s, 6H),1.64 (s, 3H), 1.01 (m, 6H).

[0673] Step 2

[0674](2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester

[0675] In a manner similar to the procedure of Example 49, Step 6 therewas obtained from4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol(0.90 g, 1.87mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester(0.67 g, 3.73 mmol), triphenylphosphine (0.98 g, 3.73 mmol),diethylazodicarboxylate (0.59 mL, 3.73 mmol), and anhydrous benzene (10mL) at 87° C. for 6 h gave the title compound as a solid (0.46 g, 38%):NMR (DMSO-d6): δ 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.47-7.45 (m, 2H),7.34 (d, 4H), 7.32-7.26 (m, 1H), 7.00 (d, 2H), 4.80 (t, 1H), 3.74 (s,2H), 3.58 (s, 3H), 3.36-3.25 (m, 2H), 2.55 (q, 4H), 2.24 (s, 3H), 2.19(s, 3H), 1.59 (s, 3H), 1.03 (t, 6H); MS(+ESI): [M+H]⁺, 1 bromine isotopepattern, 644/646; Anal. Calc. for C36H38BrNO3S: C, 67.07 H, 5.94, N,2.17. Found: C, 66.73, H, 5.93, N, 2.15.

[0676] Step 3

[0677](2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid

[0678] In a manner similar to the procedure of Example 49, Step 7 therewas obtained from(2R)-2-[4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid methyl ester (0.35 g, 0.98 mmol), aqueous potassium hydroxide (1.95mL of a 1 N solution, 1.95 mmol), tetrahydrofuran (9 mL), and methanol(3 mL) the title compound as a solid (0.35 g, >100%): NMR (DMSO-d6): δ12.90 (br s, 1H), 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.50-7.43 (m, 2H),7.37-7.31 (m, 4H), 7.28-7.24 (m, 1H), 7.00 (s, 2H), 4.72 (t, 1H), 3.74(s, 2H), 3.38-3.25 (m, 2H), 2.60-2.53(q, 4H), 2.26 (s, 3H), 2.23 (s,3H), 1.60 (s, 3H), 1.02 (t, 6H); MS(−ESI): [M−H]⁻, 1 bromine isotopepattern, 628/630; Anal. Calc. for C35H36BrNO3S: C, 66.66, H, 5.75, N,2.22. Found: C, 66.95, H, 5.99, N, 2.26.

Example 88

[0679](2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid

[0680] This compound was prepared in a manner similar to Example 87using appropriate starting materials to afford the title compound as ayellow solid: (DMSO-d6): δ 13.00 (br s, 1H), 8.18 (d, 1H), 7.63-7.60 (m,1H), 7.46-7.44 (m, 2H), 7.36-7.24 (m, 5H), 7.06 (s, 2H), 4.46 (t, 1H),3.71 (s, 2H), 3.38-3.34 (m, 2H), 3.25 (d, 2H), 2.54 (q, 4H), 1.52 (s,3H), 1.13 (d, 6H), 1.06 (d, 6H), 1.00 (t, 6H); MS(−ESI): [M−H]⁻, 1bromine isotope pattern, 684/686; Anal. Calc. for C39H44BrNO3S: C,68.21, H, 6.46, N, 2.04. Found: C, 68.04, H, 6.52, N, 1.92; AnalyticalHPLC indicates a major component (97.4%).

What is claimed is:
 1. A compound of formula I having the structure

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂CO₂R^(1′); R^(1′) is hydrogen or alkyl of 1-6 carbon atoms Eis S, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3- 1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶, —CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷, R^(7a) are each,independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R^(6b)is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbon atoms or aryl;R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6carbon atoms; Z¹ and Z² are each, independently, hydrogen, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof.
 2. The compound according to claim 1, wherein Ar is

A is hydrogen or halogen B and D are each, independently, hydrogen,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbonatoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR; R ishydrogen or alkyl of 1-6 carbon atoms; E is S, or O; X is hydrogen,halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino,NR²R^(2a), NR²COR^(2a), cycloalkylamino, morpholino, alkylsulfanyl of1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, or2-N,N-dimethylaminoethylsulfanyl; R¹, R^(1a) R², R^(2a), R³, and R^(3a)are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of6-12 carbon atoms, or aryl; Y is hydrogen, halogen, OR³, SR³, NR³R^(3a),or morpholine; C is hydrogen, halogen, or OR⁴; R⁴ is hydrogen, alkyl of1-6 carbon atoms, —CH(R⁵)W, —C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione,—CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶, —PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶,—(CH₂)_(p)COCO₂R⁶, —(CH₂)_(p)CH═CHCO₂R⁶, —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶; R⁵is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl); W isCO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶,R^(6a), R^(6b), R⁷, R^(7a), and R^(7b) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, or aryl; Z¹ and Z² are each,independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro,amino, —NR¹R^(1a), —NR¹COR^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unithaving the formula —CH═CR⁹—CR¹⁰═CH—; R⁹ and R¹⁰ are each, independently,hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; q is 1 to 4; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 2, wherein A is hydrogen; B and D are each, independently,halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,or cycloalkyl of 3-8 carbon atoms; E is S or O; X is hydrogen, halogen,alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN,alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms,arylsulfanyl; Y is hydrogen, —NR¹R², or morpholine; R¹and R² are each,independently, hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12carbon atoms, or aryl; C is OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbonatoms, —CH(R⁵)W, or 5-thiazolidine-2,4-dione; R⁵ is hydrogen, alkyl of1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(3-1H-indolyl), —CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl); W is —CO₂R⁶, —CONH₂, —CONHOH,5-tetrazole, —PO₃(R⁶)₂, or —CONR⁶CHR⁶CO₂R⁶; R⁶ is hydrogen or alkyl of1-6 carbon atoms; Z¹ and Z² are taken together as a diene unit havingthe formula —CH═CH—H═CH—; or a pharmaceutically acceptable salt thereof.4. The compound of claim 1, which is(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 5. The compound ofclaim 1, which is(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 6. The compound ofclaim 1, which is(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 7. The compound ofclaim 1, which is(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 8. The compound ofclaim 1, which is[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid or a pharmaceutically acceptable salt thereof.
 9. The compound ofclaim 1, which is(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 10. The compound ofclaim 1, which is(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 11. The compound ofclaim 1, which is(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 12. The compound ofclaim 1, which is(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 13. The compound ofclaim 1, which is(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 14. The compound ofclaim 1, which is(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 15. The compound ofclaim 1, which is(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid or a pharmaceutically acceptable salt thereof.
 16. The compound ofclaim 1, which is(S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid or a pharmaceutically acceptable salt thereof.
 17. The compound ofclaim 1, which is2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 18. The compound ofclaim 1, which is(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid or a pharmaceutically acceptable salt thereof.
 19. The compound ofclaim 1, which is[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 20. The compound ofclaim 1, which is2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenolor a pharmaceutically acceptable salt thereof.
 21. The compound of claim1, which is2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenolor a pharmaceutically acceptable salt thereof.
 22. The compound of claim1, which is(R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 23. The compound ofclaim 1, which is(R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 24. The compound ofclaim 1, which is(2R)-2-[4-9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid,
 25. The compound of claim 1, which is(R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid,
 26. The compound of claim 1, which is{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;
 27. The compound of claim 1, which is{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid
 28. The compound of claim 1, which is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 29. The compound ofclaim 1, which is(2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 30. The compound ofclaim 1, which is{(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid or a pharmaceutically acceptable salt thereof.
 31. The compound ofclaim 1, which is(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 32. The compound ofclaim 1, which is(R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid or a pharmaceutically acceptable salt thereof.
 33. The compound ofclaim 1, which is(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid or a pharmaceutically acceptable salt thereof.
 34. The compound ofclaim 1, which is(R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 35. The compound ofclaim 1, which is2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol or apharmaceutically acceptable salt thereof.
 36. The compound of claim 1,which is(R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 37. The compound ofclaim 1, which is(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 38. The compound ofclaim 1, which is(2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 39. The compound ofclaim 1, which is 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol;4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;4-(9-bromo-3-methyl-2-morpholin-4-yl)methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate;4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;2-amino-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2-amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-aceticacid;(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenoxy]-propanoicacid;2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenol;(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid; (R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionic acid;(R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid;3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamine;or[3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid;(2R)-2-[4-(9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid; 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol;4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid; 2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenol;Acetic acid2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenyl ester;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionic acid;4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid;4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyramide;4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol;[9-Bromo-4-(4-methoxy-3,5-dimethylphenyl)-3-methylnaphtho[2,3-b]thien-2-yl]methylacetate;4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenylacetate; Acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenylester;2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 40. The compound ofclaim 1, which is acetic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester; acetic acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;methanesulfonic acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester, methanesulfonic acid4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester; aceticacid4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenylester;(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid methyl ester;[3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-hydroxy-phenyl]-carbamicacid tert-butyl ester;9-bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-b]thiophene;or[3-bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid methyl ester.
 41. A method of treating metabolic disorders mediatedby insulin resistance or hyperglycemia in a mammal in need thereof whichcomprises administering to said mammal, a compound of formula I havingthe structure

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂CO₂R^(1′); R^(1′) is hydrogen or alkyl of 1-6 carbon atoms Eis S, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3- 1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶, —CH₂OCHR^(7b)CO₂R⁶or —CH₂Br,—CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷, R^(7a) are each,independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R^(6b)is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbon atoms or aryl;R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6carbon atoms; Z¹ and Z² are each, independently, hydrogen, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof.
 42. A method of treating or inhibiting type II diabetes ina mammal in need thereof which comprises administering to said mammal, acompound of formula I having the structure

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)COCO₂R, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹; R¹ ishydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,or CH₂CO₂R^(1′); R^(1′) is hydrogen or alkyl of 1-6 carbon atoms E is S,SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbonatoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbonatoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), pyridyl), —CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)Co₂R⁶, —CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷, R^(7a) are each,independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R^(6b)is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbon atoms or aryl;R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6carbon atoms; Z¹ and Z² are each, independently, hydrogen, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof.
 43. A method of modulating glucose levels in a mammal inneed thereof which comprises administering to said mammal, a compound offormula I having the structure

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂CO₂R^(1′); R¹ is hydrogen or alkyl of 1-6 carbon atoms E isS, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbonatoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbonatoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or (CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen, alkylof 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶, —CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷, R^(7a) are each,independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R^(6b)is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbon atoms or aryl;R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6carbon atoms; Z¹ and Z² are each, independently, hydrogen, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof.
 44. A pharmaceutical composition which comprises acompound of formula I having the structure

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂COR^(1′); R¹ is hydrogen or alkyl of 1-6 carbon atoms E isS, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6 carbonatoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbonatoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbonatoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms,aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethylsulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms,—CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3- 1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶, —CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷, R^(7a) are each,independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R^(6b)is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbon atoms or aryl;R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6carbon atoms; Z¹ and Z² are each, independently, hydrogen, halogen, CN,alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹-CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof..